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Annals of Surgical Oncology 9:617-624 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

The Clinical Efficacy of Neoadjuvant Chemotherapy in Squamous Esophageal Cancer: A Prospective Nonrandomized Study of Pulse and Continuous-Infusion Regimens With Cisplatin and 5-Fluorouracil

A.C.W. Chan, MD, D.W.H. Lee, FRCS(Ed), J.F. Griffith, FRCR, S.F. Leung, FRCR, Y.H. Lam, FRCS(Ed), C.C.H. Lam, B Nursing, J.Y.W. Lau, FRCS(Ed), E.K.W. Ng, MD and S.C.S. Chung, MD

From the Departments of Surgery (ACWC, JYWL, DWHL, YHL, EKWN, CCHL, SCSC), Diagnostic Radiology (JFG), and Clinical Oncology (SFL), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

Correspondence: Address correspondence and reprint requests to: Professor S. C. Sydney Chung, Department of Surgery, Prince of Wales Hospital, Shatin, NT, Hong Kong; Fax: 852-2637-7974; E-mail: sydneychung{at}cuhk.edu.hk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We evaluated cisplatin and 5-fluorouracil as preoperative adjuvant chemotherapy for patients with locally advanced squamous esophageal cancer and compared two different infusion regimens. The outcomes were also compared with those of our historical control patients treated by surgery alone.

Methods: From 1991 to 1997, 83 consecutive esophageal cancer patients underwent surgical exploration after completion of two cycles of cisplatin and 5-fluorouracil chemotherapy regimens, either in pulse or in continuous infusion cycles. Outcomes were compared with those of 76 historical control patients. Both groups were comparable in demographic characteristics and tumor stages. The resection rates, operative morbidity, mortality, and survival rates were compared.

Results: Partial response was achieved in 50% of patients who received chemotherapy. There was no chemotherapy-related mortality. The resection, morbidity, and mortality rates and median survival between the surgery-alone group and the chemotherapy group were 71.1% vs. 82%, 51% vs. 55%, and 4% vs. 10.8%, 12.0 vs. 13.5 months, respectively (P > .05). There was also no statistically significant difference between the two regimens.

Conclusions: Preoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil infusion, in pulse or continuous regimens, followed by surgery for squamous esophageal cancer patients had no added benefit in the overall survival.

Key Words: Neoadjuvant chemotherapy • Squamous esophageal cancer • Cisplatin • 5-Fluorouracil


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal carcinoma is notorious for its grave prognosis. In the absence of identifiable distant metastatic disease, the depth of tumor invasion and the presence of nodal metastases are the two most reliable independent prognostic indicators.1,2 The 5-year survival for early-stage disease (stage I) ranges from 60% to 75% in most published series.3 However, in countries such as Hong Kong, where no screening program is in practice, most patients present late, with intolerable dysphagia and with an advanced tumor stage of T3 or T4N1. The survival outcomes of these patients are anticipated to be poor when they are treated by surgery alone.4–6 To improve the survival of these patients, adjuvant therapy in addition to surgery is needed.

Squamous cell carcinoma of the esophagus has been shown to be chemosensitive, particularly to the combination of cisplatin- and 5-fluorouracil–based chemotherapy regimens.7–9 Neoadjuvant chemotherapy before surgery has the advantages of downstaging the tumor before surgery and improving the resection rate. Indeed, an overall 50% to 65% partial response rate has been reported with isolated cases of complete remission, but the survival benefit has not been proven in randomized trials.10–13 Nevertheless, new drugs, new combinations, and new regimens are currently being experimented with. In this article, we report our results on the use of preoperative chemotherapy with cisplatin and 5-fluorouracil, with pulse or continuous-infusion regimens, in patients with potentially operable squamous cell esophageal cancer and compared these results with those of a historical control group of patients treated by surgery alone in a single institution.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From January 1991 to July 1997, 83 patients were recruited into our phase II neoadjuvant chemotherapy study. Our preoperative staging protocol included upper endoscopy, flexible bronchoscopy, ultrasound of the abdomen, and computed tomography (CT) of the thorax and upper abdomen. From January 1996 onward, ultrasound of the neck was added to our protocol to evaluate neck nodal status, and fine-needle aspiration cytology was performed for suspicious or malignant-looking nodes.14 The inclusion criteria for the chemotherapy study were the following: patients with potentially resectable middle- and lower-third squamous esophageal cancer, or patients with T4 tumor stage on CT scan if bronchoscopy showed no tracheobronchial invasion; age younger than 75 years; Karnofsky score >70%; and creatinine clearance >50 ml/min. Patients with metastatic disease (M1), who are medically unfit for thoracotomy, and those who did not consent to the study were excluded. The study was approved by the Clinical Ethical Committee of the university and the hospital.

Chemotherapy Regimen
Two chemotherapy regimens (pulse or continuous-infusion cycle) were used in this series. In the early phase of the trial, 50 patients received 2 preoperative cycles of cisplatin (100 mg/m2 intravenous bolus) on day 1 and a 5-fluorouracil infusion (1000 mg/m2/24 h) from days 2 to 6, at 3-week intervals.

The regimen was changed to a continuous-infusion regimen in the later phase of the trial because promising results were reported on the use of a continuous-infusion regimen in advanced gastroesophageal cancer.15,16 A total of 33 patients received 2 cycles of cisplatin (60 mg/m2 intravenously) on days 1 and 22 and received a continuous infusion of 5-fluoruracil (200 mg/m2/24 h) via a syringe-driver pump from days 1 to 21 and days 22 to 42. For this purpose, a single-lumen Hickmann catheter was placed into the superior vena cava under local anesthesia for continuous intravenous access.

All patients were closely monitored for chemotherapy adverse effects and toxicity. An enteral nutritional supplement would be offered to patients via a fine-bore feeding tube if this was deemed to be necessary.

Assessment of Chemoresponse
In addition to pathologic examination of the resected esophageal specimen after surgery, esophageal tumor sizes were also assessed by spiral CT scan by using a modified CT protocol as described previously.17,18 Briefly, the patient was scanned in a prone position with the esophagus distended by simultaneous administration of intravenous hyosine and an oral effervescent solution. Spiral CT scan of the chest and upper abdomen was performed with 10-mm collimation, a 1 cm/sec table feed, and a 1:1 pitch. The tumor volume was calculated from the total surface area and length of the tumor. The accuracy of this volume-assessment method was validated in our previous study.17

Historical Control Patients
From January 1985 to December 1990, 76 consecutive patients with squamous esophageal cancer underwent esophagectomy without preoperative or postoperative adjuvant therapy. The staging work-up was similar to that of the chemotherapy group, except for the neck ultrasound. The selection criteria for surgical exploration in these patients were the same as in the chemotherapy group. Their data were retrieved from the prospective esophageal database. The demographic data and the tumor characteristics were comparable to those of the chemotherapy group (Table 1).


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  		TABLE 1. Demographic data, tumor location, tumor stage, and operations in surgery and chemotherapygroups
 
Surgery
In general, two-stage Ivor-Lewis esophagectomy with stomach pull-up was performed for most patients by using our synchronous two-team approach.6 Paraesophageal and mediastinal lymph nodes were cleared en bloc with the esophagus, but three-field lymphadenectomy was not performed. The whole stomach was pulled into the right chest through the hiatus and resided in the right posterior mediastinum at the end of the operation. Three-stage esophagectomy was performed for patients with more proximal extension of the upper esophagus. Esophago-gastric anastomosis was routinely performed with the circular stapler except for the occasional neck anastomosis. Thoracoscopic esophagectomy was performed in eight patients. The surgical resection was deemed as curative when no macroscopic tumor was left in situ. For patients who received chemotherapy, esophagectomy was performed within 2 weeks after the completion of chemotherapy, provided that the patient was fit for surgery.

Statistical Analysis
The treatment outcomes of the two groups of chemotherapy patients were then compared with those of the surgery group. Fisher’s exact test, two-sided {chi}2 tests, and Students’ t-tests were used to compare the demographic data and the outcomes of both groups, as well as for subgroup analysis, when appropriate. The survival analysis was performed with Kaplan-Meier curves and log-rank test comparisons.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
During this period, 83 patients with squamous esophageal cancer were operated on after the completion of chemotherapy. The clinical demographic data, types of operation, tumor location, cell differentiation, and tumor stage are listed in Table 1. Although this study was not conducted in a randomized, controlled fashion, the surgery-alone group was comparable to the chemotherapy groups in demographic data and tumor characteristics. Both chemotherapy groups were also similar in all aspects.

Surgery and Postoperative Complications
Esophagectomy was performed in 64 of 76 patients (84%) in the surgery group and 78 of 83 patients (94%) in the chemotherapy group (Table 2). In the surgery group, 54 patients (71%) had curative resection, and 10 patients (13%) had palliative resection with macroscopic tumors left behind. In the rest of the surgery group, five patients underwent gastric bypass operations because of local infiltration into the adjacent organs, and seven patients had explorations only. Of the chemotherapy group, curative resection was possible in 68 patients (82.9%), with 10 palliative resections (12%), 4 bypass operations, and 1 exploration only. The curative resection rate after chemotherapy was not statistically significant compared with the surgery-alone group (P = .13).


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  		TABLE 2. Types of operations, morbidity, and mortality in three groups ofpatients
 
The overall postoperative complication rate was 51% in the surgery group and 54% (72 of 133) in the chemotherapy groups (60% in the pulse regimen group and 48.5% in the continuous group; Table 2). The overall rate of anastomotic leakage was 3% (5 of 159) in our series. Major complications in both groups arose from the lungs, and the high percentage of respiratory infections was probably due to the aged population of patients and the immunosuppressive effect of chemotherapy. Postoperative wound infections were more common in the chemotherapy group than the surgery group (12% vs. 5.3%), but the difference was not statistically significant (P = .17). The operative mortality rates of both groups were not significantly different (surgery, 4%;chemotherapy, 10.8%; P = .14). The main causes of death were respiratory failure and prolonged lung sepsis.

Complications Related to Chemotherapy
In general, chemotherapy was well tolerated. A total of 162 cycles were given to the studied patients. Anorexia and nausea were encountered in approximately one fifth of patients on the first 2 days of induction (Table 3). Neutropenia was significantly more common in patients receiving the continuous-infusion regimen; it typically occurred at the end of the first course and in the first week of the second course (P < .001). According to the common toxicity criteria grading system, the white blood cell count in the majority of patients remained >=2.0 x109/L, and chemotherapy could be continued. Only one patient had a white blood cell count of <2.0 x 109/L, and this resolved after chemotherapy was withheld for a few days. Fever and sepsis were more often seen in patients receiving a continuous regimen, in whom the Hickmann catheter acted as the potential source. The source of sepsis could not be identified in seven cases, but all resolved with broad-spectrum antibiotics. All patients completed the two cycles in the continuous-regimen group, whereas three patients opted to decline further chemotherapy in the pulse group and one patient with borderline renal function was withdrawn. In this series, there were no life-threatening complications related to the chemotherapy.


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  		TABLE 3. The toxicity effect of pulse and continuous chemotherapyregimens
 
Tumor Response to Chemotherapy
From 1994 on, we used the spiral CT scan to document the tumor volume change after completion of chemotherapy. For these patients with CT documentation, 39 of 45 (87%) tumors were reduced in volume after chemotherapy, 3 tumors were static, and 3 patients had disease progression with an increase in tumor volume. Overall, 50% of patients had a partial response (>50% reduction in tumor volume). The tumor stage was downstaged in 10 of 45 patients (22%) on CT scan, with no change in N stage. Of these, five tumors deemed not resectable with prechemotherapy CT criteria were successfully resected with a clear margin. Only three patients had complete pathologic regression (pulse, n = 1; continuous, n = 2; 3.6% of the total) confirmed on sequential histological sections of the resected specimens. Despite adjuvant therapy, 86.7% of resected specimens were histologically stage II and III disease, similar to the 84% of tumors in the surgery-alone group.

Recurrence and Survival
The Kaplan-Meier survival curves of the surgery-alone and the surgery-with-chemotherapy groups and of the pulse regimen versus the continuous-infusion regimen are shown in Figs. 1 and 2. The survival rate for the surgery-alone group was 65% at 1 year, 35% at 3 years, and 16% at 5 years, with a median survival of 16.7 months. As shown in Fig. 1, there was no additional survival benefit with these two chemotherapy regimens. The overall survival rate for the chemotherapy group was 55% at 1 year, 27% at 3 years, and 23% at 5 years, with a median survival of 13.5 months. The median disease-free interval for the surgery group and the surgery-plus-chemotherapy group was 10 and 9.2 months, respectively. There was no significant association of the tumor volume reduction with the survival or the disease-free interval. Forty-three (52%) patients in the chemotherapy group had recurrence, and among these, 16 (19%) patients had local recurrence, 22 (27%) had distant metastasis, and 5 (6%) had both local recurrence and distant metastasis. The only prognostic factor in determining the survival and recurrence was the pathologic staging; the survival and recurrence interval for tumor stages I and II was significantly better than for tumor stages III and IV (P = .0006 and P = .02, respectively).



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  		FIG. 1. Survival curves of the surgery and chemotherapy groups.

 


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  		FIG. 2. Survival curves of the pulse and continuous chemotherapy groups.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Cisplatin- and 5-fluorouracil–based chemotherapy regimens are often used as adjuvant therapy for squamous cell carcinoma of the esophagus. Nonrandomized trials7–9 and randomized trials10–12,19 have reported a 40% to 65% partial response rate, but only one randomized trial demonstrated a survival benefit solely in that subgroup of patients who responded to chemotherapy.11 The earlier randomized trials recruited only a small number of patients and thus may not be powered to demonstrate small outcome differences. Kelsen et al.13 reported a multicenter trial that compared preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer (54% adenocarcinoma and 46% squamous cell carcinoma) in 440 eligible patients with a median follow-up of 46.5 months. The chemotherapy regimen was three cycles of cisplatin and 5-fluorouracil before the operation and two additional postoperative cycles in those patients who had stable or responsive disease. Eighty-three percent of patients in the chemotherapy-plus-surgery group completed at least two cycles of preoperative chemotherapy, but only 38% received two cycles of postoperative chemotherapy. There was no difference between the two groups in median survival (14.9 months in the chemotherapy-plus-surgery group and 16.1 months in the surgery-alone group). Moreover, the addition of chemotherapy did not change the rate of local recurrence or distant metastasis.

In contrast, the Medical Research Council in the United Kingdom recently reported, in abstract form, an early favorable result from a large-scale randomized trial.20 This trial recruited 802 patients who were randomized to receive two 4-day cycles of cisplatin and fluorouracil infusion before surgery or surgery alone. Again, the majority (66%) of tumors were adenocarcinomas involving the lower esophagus. The median survival was 17.4 months in the chemotherapy-plus-surgery group compared with 13.4 months in the surgery-alone group. Also, the 2-year survival rate was 45% and 35% in the chemotherapy-plus-surgery group and the surgery-alone group, respectively. It is interesting to note that the chemotherapy-plus-surgery group achieved a higher complete resection rate (84%) compared with the surgery-alone group (71%), but with no additional postoperative mortality. Nonetheless, we are still awaiting the final results before we can draw any definite conclusion from this trial.

In this study, we evaluated the adjuvant use of cisplatin and 5-fluoruracil infusion in two different modes of regimens and compared the outcomes with those of patients who had surgery alone in a single institution. Our study group was slightly different from other reported trials in a few respects. First, all tumors were of squamous cell origin, and 90% were located in the middle and lower third of the esophagus. Standard subtotal esophagectomy with mediastinal lymph node clearance was performed by a single team, who managed the chemotherapy at the same time. We elected not to perform three-field lymph node dissection for our patients, because these tumors were of intrathoracic origin, and neck node metastasis would therefore indicate M1 disease, which generally has a poor prognosis. To include these patients in the neoadjuvant chemotherapy trial would have diluted the efficacy of the chemotherapy, which may also be the reason for the disappointing results in previously published randomized trials. Matsubara et al.21 demonstrated that preoperative detection of a positive cervical lymph node strongly predicted survival in squamous esophageal cancer. The 5-year survival rate for negative lymph nodes was 70%, compared with 20% in positive nodes. The use of neck ultrasound with fine-needle aspiration as a routine preoperative staging procedure helps to exclude these patients from entering onto future trials. Our study’s patient group therefore represented a highly selected homogenous group of patients in terms of disease status. Second, preoperative documentation of tumor response was conducted in a more objective manner by measuring the tumor volume with our published CT technique.17,18 The technique has been validated in a previous study, with good correlation. To date, there is no other reliable method of assessing tumor response to chemotherapy before resecting the esophagus for pathologic grading. Dysphagia grading improvement is subjective and is affected by many factors. Endoscopic assessment of the tumor after chemotherapy may be biased by different operators and the lack of objective criteria. The same problem is encountered in endoscopic ultrasound measurement for tumor size and stage.22,23 Comparing the tumor stage on preoperative CT scan with the pathologic stage of the resected specimen is not a true comparison, because the accuracy of CT staging is questionable in some aspects. Our study also demonstrated that the accuracy of the CT stage decreased after chemotherapy, especially in T4 tumors.18 Our technique of comparing tumor volume before and after chemotherapy is objective, reproducible, and universally applicable. Third, there is no similar comparison study on the use of pulse 5-fluorouracil infusion regimens and continuous-infusion regimens in patients with the same malignancy under the same setting.

In this study, we compared the chemotherapy patients with our historical patients who received surgery alone. One potential bias was that the chemotherapy group would do better as survival and outcomes improved over time because of improved perioperative and intensive care management. Although this historical control group of patients was operated on in the era before we started our chemotherapy trial, they were selected for surgical exploration on the basis of similar operability criteria and were operated on by the same surgical team. The demographic characteristics and the distribution of disease stages were comparable. It is conceivable that this historical group could serve as a baseline comparison model for our phase II trial. Nonetheless, it is important to note that, even when compared with the historical control group, neoadjuvant chemotherapy failed to improve survival in this study. We must strongly emphasize that a controlled, randomized trial should be conducted to truly evaluate the benefit of any new treatment modality whenever circumstances allow.

In comparing the two modes of chemotherapy regimens, both were well tolerated, with no major life-threatening complications related to the chemotherapy. The myelosuppression toxicity and sepsis related to the Hickmann catheter occurred more often with the continuous-infusion regimen. These complications can be controlled by withholding the chemotherapy for few days and by administering antibiotics. Catheters were removed if line sepsis was suspected. There was no additional surgical morbidity and mortality as demonstrated in our series compared with the historical control group. The respiratory complication rate and anastomotic leakage rate were similar in both groups. In this study, we reported an overall 50% complication rate, mostly attributed to chest complications. In the meta-analysis review by Muller et al.,5 an overall complication rate of 36% in 46,692 resection patients was reported that included more life-threatening complications. Our respiratory complication rate was comparable to that of most recently published series.6,24,25 The operative mortality was also comparable in the two groups. The postoperative wound infection rate was not statistically greater in the chemotherapy group.

Although tumor volume reduction, as judged by CT examination, was seen in 80% of our patients after chemotherapy, partial response was seen in only 50% of patients (>50% improvement in tumor assessment) with the World Health Organization classification.26 Complete pathologic remission of the resected specimen was found in only 3.6% of patients. The overall survival and disease-free interval were not statistically different in the surgery and chemotherapy groups or between the two modes of infusion regimens. The 5-year survival rate was 20% in the surgery group and 25% in the chemotherapy group. There was no added survival benefit for patients with squamous esophageal cancer who received preoperative adjuvant chemotherapy. The pattern of recurrence in the chemotherapy group was similar to that reported by Kelsen et al.13 In this regard, we did not think neoadjuvant chemotherapy could reduce systemic recurrence. On the basis of these disappointing results, our unit and others are currently evaluating the role of other adjuvant therapies, such as concurrent chemoradiation followed by surgery.27–29

In conclusion, the use of adjuvant cisplatin and 5-fluorouracil chemotherapy with surgery in patients with squamous carcinoma of the esophagus was well tolerated. No significant improvement in tumor staging was seen in the chemotherapy group. Although most patients showed a tumor reduction on serial CT examinations after chemotherapy, this did not translate into improved survival. Other combination-modality treatments need to be explored in an effort to improve surgical outcomes.


   Footnotes
 
We evaluated the use of cisplatin and 5-fluorouracil as preoperative adjuvant chemotherapy for patients with locally advanced squamous esophageal cancer and compared two different infusion regimens.

Received for publication June 11, 2001. Accepted for publication April 10, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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