Vinorelbine and cisplatin in metastatic squamous cell carcinoma of the oesophagus: response, toxicity, quality of life and survival

T. Conroy1,+, P.-L. Etienne2, A. Adenis3, M. Ducreux4, B. Paillot5, J. Oliveira6, J.-F. Seitz7, E. Francois8, E. Van Cutsem9, D. J. T. Wagener10, F. Kohser11, S. Daamen12, M. Praet12, T. Gorlia12, B. Baron12 and J. Wils13

1Centre Alexis Vautrin, Vandoeuvre-lès-Nancy; 2Clinique Armoricaine de radiologie, St Brieuc; 3Centre Oscar Lambret, Lille; 4Institut Gustave Roussy, Villejuif; 5Hôpital Charles Nicolle, Rouen, France; 6Instituto Português de Oncologia, Lisboa, Portugal; 7Institut Paoli-Calmettes et CHU La Timone, Marseille; 8Centre Antoine Lacassagne, Nice, France; 9UZ Gasthuisberg, Leuven, Belgium; 10University Medical Center, Nijmegen, The Netherlands; 11Hôpital Pasteur, Colmar, France; 12EORTC Data Center, Brussels, Belgium; 13Laurentius Hospital, Roermond, The Netherlands

Received 25 June 2001; revised 11 September 2001; accepted 20 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population.

Patients and methods

Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30.

Results

All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23–46); the median duration of response was 6.8 months, progression-free survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement.

Conclusions

Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin–5-fluorouracil.

Key words: chemotherapy, cisplatin, oesophageal cancer, quality of life, vinorelbine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Carcinoma of the oesophagus is a disease with marked variations in geographical incidence related to etiological factors, but the probability of surviving the condition is low regardless of the setting in which it occurs: data from cancer registries of 17 European countries showed that relative survival rates between 1985 and 1989 were 33% at 1 year and 10% at 5 years [1]. The two major risk factors for squamous cell carcinoma of the oesophagus are tobacco smoking and alcohol consumption, with rates approximately five times higher for smokers than non-smokers and 20- to 50-fold greater for those with a high alcohol intake; the two factors are related but have a multiplicative effect when present together [2].

Patients with carcinoma of the oesophagus treated with surgery or radiotherapy alone have historically had 5-year survival rates <10% [3], partly because many patients undergo early dissemination of the disease. Combined chemotherapy and radiotherapy represents an important advance in the treatment of locally advanced disease, increasing 5-year survival rates to 25% [4], but the problems of management of patients who present with disseminated disease remain considerable. The repertoire of chemotherapeutic agents with activity against squamous cell carcinoma is restricted, but responses have been documented in studies utilising cisplatin, 5-fluorouracil (5-FU), vindesine, mitomycin, paclitaxel and vinorelbine (VNB) [5].

Previous studies of chemotherapy for locally advanced or metastatic squamous cell carcinoma of the oesophagus conducted by the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) have examined the activity of cisplatin alone versus cisplatin plus 5-FU in a randomised phase II trial [6] and single agent vinorelbine in an open phase II study [7]. In the randomised study, although greater activity was demonstrated for cisplatin–5-FU in combination, this was achieved at the expense of substantially increased toxicity and the group concluded that neither arm could be recommended as the standard chemotherapy for patients with advanced squamous cell oesophageal cancer. In contrast, the study of single-agent vinorelbine demonstrated worthwhile activity, with an overall response rate of 20% [95% confidence interval (CI) 8–39%] in previously untreated patients while retaining a good tolerance profile. It was therefore decided that it would be appropriate to undertake a phase II study to evaluate a combination of vinorelbine and cisplatin in this disease. The dose-schedule of the combination of vinorelbine and cisplatin selected had been tested in patients with advanced non-small-cell lung cancer, and shown to be well tolerated [8]. The trial was undertaken in the knowledge that at that time no phase III trial had ever been performed in this indication comparing active treatment with ‘best supportive care’ and that the contribution of palliative chemotherapy was not fully established.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study reported here is a phase II trial of vinorelbine plus cisplatin given as a 3-weekly schedule to evaluate the activity of this combination in patients with metastatic squamous cell carcinoma of the oesophagus. It was also intended to determine the safety of the combination, to estimate the progression-free survival and overall survival of the patient population, and to assess the quality of life (QoL).

Eligibility and evaluation
Eligibility criteria for this study included the following: age <75 years; histologically proven metastatic squamous cell carcinoma of the oesophagus previously untreated with chemotherapy; WHO [9] performance status <3; at least one measurable (bidimensional) metastase [according to 1987 TNM (tumour–node–metastasis) staging system] [10] located outside a previously irradiated area with a diameter either >=20 mm for lung metastases clear of any other structure or >=25 mm for lesions in any other location; peripheral neuropathy less than grade 2; absolute neutrophil count >=2 x 109/l; platelet count >=100 x 109/l; adequate renal and hepatic function; bilirubin <1.5 times upper limit of normal value; serum creatinine <132 µmol/l. Exclusion criteria were as follows: patients with brain or leptomeningeal involvement or with uncontrolled infection; patients with prior malignancies (other than basal cell carcinoma of the skin) except prior Tis, T1 N0 or T2 N0 squamous cell carcinoma of the head and neck; in addition, patients with tracheal involvement or angina or prior myocardial infarction, or factors preventing follow-up were excluded. All patients who entered the study gave written informed consent in a format consistent with the requirements of the Helsinki Declaration; the protocol was approved by ethics committees at all the participating countries.

Measurable disease was defined as bidimensionally measurable lesions using a ruler or calipers; ultrasonographic assessment of hepatic metastases should have been undertaken by the same operator (if possible) to ensure consistency of reporting. Evaluation of the primary oesophageal tumour was done by barium swallow oesophagogram and computerised tomography (CT) scanning with intravenous contrast. Bone metastases were assessed by isotope scanning but were not considered to be measurable disease.

Pre-treatment evaluation included physical examination and determination of performance status, complete blood counts and serum chemistry, evaluation of the primary oesophageal tumour, evaluation of liver and other metastases (by ultrasound/CT scan); documentation of prior and co-existent medical conditions and a QoL patient self-assessment. For response evaluation, examinations used to document the extent of the disease were repeated every 6 weeks (two cycles); haematology values were repeated on day 1 and 8 of each course and biochemistry values were estimated on day 1 only.

Treatment
The starting dose of vinorelbine was 25 mg/m2 administered over 5–10 min into a free-running infusion during the pre-hydration for cisplatin administration (for patients with documented cirrhosis the dose of vinorelbine was reduced to 20 mg/m2 for the first course and escalated to 25 mg/m2 if the treatment was tolerated); vinorelbine was administered on days 1 and 8 of a 21-day cycle. Cisplatin was given on day 1 at a dose of 80 mg/m2 over 30 min after pre-hydration with 2 l of fluid (0.9% saline + 30 ml KCl 10% + 12 ml MgCl2 10%) over 2 h and followed by a further 1.5–2 l post-hydration with the same electrolyte mixture. All patients received prophylactic antiemetics with a 5-HT3 antagonist and the routine use of laxative agents was encouraged. In patients with stabilisation of their disease or response at the end of the first two cycles, treatment was continued until there was documented progression or any unacceptable toxicity occurred. Response was assessed every two cycles of treatment; each patient was followed for at least 30 days after the last dose of drug or until resolution of any drug related toxicity. Patients withdrawn from the study were followed at 3-monthly intervals until death.

Dose modifications were made as follows: for haematological toxicity consisting of neutrophils <1.5 x 109/l or platelets <75 x 109/l at day 1, delay vinorelbine and cisplatin for 1 week; for neutrophils <1 x 109/l or platelets <75 x 109/l at day 8, delay vinorelbine for 1 week; hepatic toxicity at grade 3 by expanded Cancer and Leukaemia Group B (CALGB) criteria, delay vinorelbine and cisplatin and reassess weekly; hepatic toxicity at grade 4, discontinue vinorelbine and cisplatin; peripheral neuropathy or constipation at grade >=3, delay vinorelbine and reassess.

Concurrent management consisted of full supportive care including, according to each patient’s need, the use of blood and blood products, nutritional support and all other means of symptomatic relief; haemopoietic growth factors were not allowed; palliative radiotherapy to a single painful lesion using a small field was permitted on a non-target lesion at inclusion in the study, but if more extensive treatment was required, the patient was removed from the study.

Response and toxicity criteria
Only eligible patients are presented in the safety and efficacy analysis. Toxicity criteria were as defined by the expanded CALGB criteria [11]. All events occurring during chemotherapy or with a worsening grade in comparison with baseline were considered as toxicities. However, for infections investigators were asked to assess the relationship with the ongoing chemotherapy. Responses were determined according to the WHO’s recommendations [12] with amendments according to EORTC procedures [13]. In summary, responses related to measurable disease were defined as follows: complete response (CR), disappearance of all known disease determined by two observations at least 4 weeks apart; partial response (PR), decrease of at least 50% (for bidimensional lesions) or 30% (for unidimensional lesions) in the total tumour size of lesions confirmed by observations at least 4 weeks apart; no change (NC), neither 50% decrease nor 25% increase over a 6-week period; progressive disease (PD), 25% increase in the size of at least one measurable lesion or appearance of a new lesion. All responses had to be reviewed by one radiologist independent of the participating centres. Durations of response was measured from the time that the response was documented to the time at which progression was observed. The date of the response was as reviewed by the independent reviewer. The time to progression was measured from entry to the trial to the time at which progression or death without evidence of progression was observed. Overall survival was measured from the beginning of therapy to death or censored at the date the patient was last observed. Time to event end-points curves were estimated using the Kaplan–Meier technique [14].

Dysphagia and QoL assessment
The ability to swallow was expressed using a published dysphagia scale [15]: a score of 1 denoted no dysphagia; 2, trouble on deglutition of solids; 3, the ability to swallow semi-solids only; 4, the ability to swallow liquids only; and 5, complete dysphagia. The EORTC QoL core questionnaire (QLQ-C30, version 1) was used to assess QoL [16]. The QLQ-C30 consists of five functional scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, nausea/vomiting and pain), six single item scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhoea and financial impact) and a global health status/QoL scale. These scales were constructed using the scoring procedures for the EORTC Core QoL Questionnaire EORTC QLQ-C30 version 1 [17]. Scale scores were calculated by averaging items within scales and transforming average scores linearly to a 0–100 scale, with higher scores representing a higher level of functioning or a higher level of symptoms. If there were items missing within a scale, provided at least half of the items in the scale are completed, the scale score is calculated using only those items for which there were known values. The QoL assessment was planned at study entry and at the end of the second and fourth cycles of chemotherapy.

Statistical methods
Sample size was determined by the one-sample multiple testing procedure for phase II clinical trials as described by Fleming [18]. To identify a response rate of between 25% (minimum level of interesting activity) and 45% (level of activity sufficiently great to warrant further investigation) with a false positive error rate of <5% (<=0.05) and a false negative error rate of <7.5% (<0.075) requires an initial sample of 35 patients; if more than nine patients in the initial cohort have responses after a maximum of four courses the study should be extended by 25 further evaluable patients to obtain a final population of at least 60 fully evaluable patients.

QoL analysis was performed according to the EORTC procedure [17]. Distributions of scores were compared with Mann–Whitney rank test. Changes in QoL were tested using the Wilcoxon signed rank test. Both stepwise and backward logistic regression models were performed to investigate the predictive value of QoL scales for response. An exploratory prognostic factor analysis for survival was performed using rank tests for the univariate analysis and both backward and stepwise Cox’s proportional hazard regression for multivariate analysis.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 75 patients were enrolled between April 1995 and October 1998. Four patients were ineligible for the following reasons: one had tracheal involvement without metastatic disease, one because of prior myocardial ischaemia and ischaemic stroke at entry, one with a pleural abscess and one with lung cancer. Three of them started treatment. One PR, one NC and one PD were observed as best responses to treatment. The characteristics of the 71 eligible patients are shown in Table 1. Over the initial 35 patients, 10 PR were observed and therefore recruitment continued to ensure that there were at least 60 evaluable patients.


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Table 1. Patient characteristics of eligible patients at entry
 
Toxicity
Severe (grade 3 or 4) toxicities are described in Table 2; grade 3/4 neutropenia was experienced by 29 patients (41%) and anaemia by 13 (18%), but thrombocytopenia was recorded in only one patient. The most severe clinical toxicities were grade 4 vomiting in seven patients (10%) and cardiac dysrhythmia in five patients (7%). Neurotoxicity either affecting peripheral nerves or presenting as constipation was mild and infrequent. A total of 38 infection episodes were described in 32 patients. A concomitant neutropenia was observed in 70%. The infection was considered to be related to treatment in 16 patients, including grade 3 in eight patients (11%) and grade 4 in four patients (6%). One toxic death (from septicaemic shock) was reported in a 70-year-old patient with previous laryngeal cancer. This patient had pulmonary, hepatic and lymph node metastases. At day 12 of the first cycle, he presented with diarrhoea, vomiting, cough and fever; leukocyte count was 0.3 x 109/l. Despite hospitalisation, antibiotics and symptomatic treatment, the patient died 2 days later. Autopsy revealed an 8 cm necrotic pancreatic metastase.


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Table 2. Highest CALGB toxicity per patient
 
Response to therapy
The median number of cycles administered was four (range one to 12 cycles) and all eligible patients were assessable for response; the results of therapy are shown in Table 3. External review of the responses resulted in some revision of the outcomes as originally determined by the investigators (one unconfirmed PR revised to confirmed PR, three PRs revised to NC and one CR to PR), while one PR could not be confirmed by the reviewer because the hospital file was lost. All responses except one were evaluated with CT (and double-contrast barium oesophagogram for primary tumour). One response was evaluated with both CT and liver echography. Therefore, 24 of 71 patients showed an objective confirmed PR, for an overall response rate of 33.8% (95% CI 23–46). Responses were seen at all sites of disease and included responses in the primary tumour, lymph nodes, liver, lung, adrenals and skin metastases.


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Table 3. Response in all eligible patients (after external review)
 
Eight patients are registered as failures of treatment because they could not be evaluated at 6 weeks from the start of therapy including the patient who died from a septic shock: five patients died of other causes before completing two cycles (two sudden deaths at home, one digestive haemorrhage, one performance status impairment, one off treatment after cycle 1 due to vomiting, dehydration and creatinine increase), and two patients deteriorated sufficiently that no further treatment could be offered after cycle 2. The median overall survival of the whole group was 6.8 months (95% CI 5.6–9.8 months) and the progression-free survival time was 3.6 months (95% CI 3–4.5 months). Kaplan–Meier curves are shown together in Figure 1. Median time to response was 1.5 months (95% CI 1.3–2.5 months). The median duration of response for the 24 responders was 6.8 months (95% CI 5–10.6 months).



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Figure 1. Progression-free survival and overall survival.

 
Two patients are long-term survivors; one had multiple pulmonary metastases and achieved a PR at cycle 4, which continues at >5 years. Owing to the unusual duration of response, all CT scans and X-rays were reviewed and two radiological reviewers confirmed the diagnosis of lung metastases and the response. A second patient with locally advanced oesophageal cancer and lymph nodes metastases was considered during laparotomy as unresectable. A PR was confirmed at cycle 6. After cycle 9, a second look was performed by the same surgeon. An R0 resection was achieved. A pathological CR was achieved in the primary tumour, but a few residual tumour cells were seen in lymph nodes. The patient is still alive without progression after 3 years of follow-up.

Dysphagia and QoL assessment
Forty-two (81%) of 52 patients had dysphagia before treatment. Five patients did not reach the third cycle. At first evaluation, of 37 patients with assessable dysphagia, four (11%) noted improvement and 17 (46%) experienced resolution of dysphagia on treatment. During protocol therapy, three patients (8%) reported improvement and 26 (70%) noted resolution of dysphagia.

Patient compliance to QoL assessment was 83% at baseline, 95% for the second assessment and dropped to 61% for the third assessment. Patients with low QoL scores dropped out earlier than patients with high QoL scores, which indicates a selection bias in the QoL analysis at the second and fourth cycles. Reasons for dropout were death, progression of the disease and toxicity. According to a study conducted by Osoba et al. [19], patients with a mean change in scores of 5–10 points (on the 0–100 range) reported ‘a little’ change in QoL. A ‘moderate change’ in QoL was reflected in scores changing by 10–20 points; and patients that reported ‘very much’ change in QoL had mean scores that changed by >20. In the 46 patients who completed a questionnaire both at baseline and at cycle 2 there was ‘a little’ improvement in QoL score from baseline to cycle 2, followed by ‘a little’ decrease at cycle 4 for the 22 patients who completed all three assessments. At first assessment after the second cycle, 11 patients (25%) and 12 patients (27%) reported a large improvement (>=20 points) in global health status/QoL and in physical functioning, respectively. Ten patients (16%) reported improvement (>=20 points) in pain, 15 (33%) in insomnia and 11 (26%) in appetite loss. Overall QoL data (changes >=10 points) are shown in Table 4.


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Table 4. Changes in QoL scores from baseline to after the second cycle: at least ‘a moderate’ change
 
The most responsive scales after the second cycle were physical and role functioning, fatigue, dyspnoea, insomnia and appetite loss. After the fourth cycle, pain, social functioning_and global health status/QoL scores also improved. Mean score differences between baseline and cycle 2 were +6 for global health status/QoL, +7.5 for insomnia and +8 for financial problems. According to the Wilcoxon signed rank test, only two scales have P values <0.01: insomnia (P = 0.0016) and financial problems (P = 0.0054). Owing to sample size limitations (n = 46), P values are only indicative. A comparison of baseline QoL scores with the EORTC references values [20] coming from a Bristol University series indicated that the two oesophageal cancer populations were quite similar. However, the trial population had more nausea and vomiting and higher social functioning scores at inclusion.

An univariate analysis was performed to identify prognostic factors for response. No P values <0.01 were identified for the baseline and the second cycle assessments. For the fourth cycle assessment, the most sensitive scales (P values <0.01) appear to be physical, role and emotional functioning, global health status/QoL and fatigue. Figure 2 shows the sequence of global health status/QoL scores divided by response, and although the number of observations is limited, especially in the group with PD, an analysis of the degree of change [16] seems to confirm that response to treatment is associated with improvement in QoL score and also that a low QoL score at entry seems more likely to be associated with lack of response or progression of disease. An exploratory prognostic factor analysis for survival was performed. In univariate analysis, three scales had log-rank P values <0.05: physical functioning (P = 0.023) and fatigue (P = 0.011). Two factors were retained after multivariate analysis, physical functioning (P = 0.03) and social functioning (P = 0.03).



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Figure 2. Prognostic factor analysis for response.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The EORTC has conducted a series of studies [6, 7] in the treatment of squamous cell carcinoma of the oesophagus, which are summarised in Table 5. Although the passage of time may have rendered these studies not strictly comparable because of the evolution of imaging techniques, and other potential bias related to changes in the management of these patients, they all represent multicentre trials with external review of responses in an attempt to improve consistency. Greater standardisation of trials and better comparability between studies may be achieved in the future by the application of the recommendations of the RECIST guidelines [21], which also simplify the measures of unidimensional lesions as oesophageal primary tumour on oesophagogram. This study only included patients with measurable disease. According to the EORTC procedures, eligible patients should have metastases >2.5 cm in largest diameter (>=2 cm for lung metastases). These restrictive criteria might explain the long duration of the trial and the poor characteristics of the patient population, but they have resulted in a homogenous population of patients with metastatic squamous cell carcinoma of the oesophagus. Most other recent trials have included both locally advanced unresectable tumours and metastatic disease [6, 2229], as well as a mixture of adenocarcinomas and squamous cell carcinomas [2224, 2630].


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Table 5. EORTC studies of chemotherapy for squamous cell carcinoma of the oesophagus
 
Treatment of patients with metastatic squamous cell carcinoma of the oesophagus continues to present significant clinical problems. The heavy use of tobacco and alcohol together with the characteristically late presentation of the disease results in a patient population that is frail, and tolerates therapy poorly. One randomised study compared cisplatin– 5-FU for a maximum of eight cycles with no chemotherapy in 156 patients. There was no difference in survival but an increase in complications in the chemotherapy arm, which resulted in toxic deaths in 6% of the population [25]. In some studies, chemo-induced toxic deaths occurred in 10–14% of the patients [6, 27].

Our data show that the combination of vinorelbine and cisplatin is safe in patients with oesophageal squamous cell carcinoma, despite the frequent occurrence of severe neutropenia. No grade 4 neurotoxicity was observed despite the association of two potentially neurotoxic drugs, and grade 3 peripheral neurotoxicity occurred in only 5% of the patients. Alopecia and mucositis were infrequent. One-third of the patients achieved a confirmed PR with a median of 6.8 months duration.

New chemotherapeutic agents, especially taxanes and topoisomerase I inhibitors, are being tested in advanced squamous cell oesophageal cancer. High-dose paclitaxel (250 mg/m2) was used in 18 patients. However, an unspecified number of patients had locoregional rather than metastatic disease. Five patients (including three with measurable disease) achieved a PR, with a response rate of 28% (95% CI 7% to 49%). The median duration of response was 3.9 months [22]. Toxicity, however, was substantial: 86% of patients experienced grade 3/4 myelosuppression and 100% alopecia. In another study, paclitaxel was used as a weekly 80 mg/m2 1-h infusion; the response rate in 58 evaluable patients was 14.5% (95% CI 6% to 23%) [30]. With a three-drug combination of paclitaxel– cisplatin–5-FU, problems with toxicity required a reduction in the dose of 5-FU [26]; the overall response rate was 50% of 30 patients. A paclitaxel and cisplatin combination (75 mg/m2) was tested in 38 patients [27]; responses occurred in 13/28 (44%) evaluable patients with adenocarcinoma and one of four patients with squamous cell carcinoma; median duration of response was 3.9 months, but four patients died from chemotherapy-related complications and half of the patients required hospitalisation for toxicity. A second study with paclitaxel and cisplatin every 2 weeks achieved a 50% response rate in 14 evaluable patients [29]. Docetaxel has also been evaluated at a dose of 100 mg/m2 every 3 weeks in 27 patients with locally advanced squamous cell carcinoma: there were seven early deaths [31]. One CR and seven PR (30%) were achieved. A study of weekly irinotecan and cisplatin achieved major responses in eight of 12 with squamous cell carcinoma; however, the median duration of response was brief (3.8 months) [28]. Some of these studies did not require confirmation of response 4 weeks apart [22, 2628] nor extramural review of responses [2228]. This could partly explain in some cases the description of a high response rate associated with a rather short duration of response.

The possibility of improving the response rate of patients with advanced squamous cell carcinoma of the oesophagus by intensifying chemotherapy would appear to be limited by the increase in the rate of severe toxicity which is a major problem in this patient population. Studies of vinorelbine–cisplatin– 5-FU in advanced head and neck cancer [32, 33] or adenocarcinoma of the oesophagus [34] have apparently demonstrated the feasibility of this combination, but some investigators have warned of severe mucositis [35], which would be a limiting factor.

At the time the protocol was written, no data were available on QoL during chemotherapy of metastatic oesophageal cancer. Therefore, QoL assessment was included, in order to better describe the consequences of the disease and treatment on QoL. Unfortunately, the EORTC QLQ-C30 does not include any item on dysphagia. Compliance with QoL assessment in our trial was fair, but dropped to 61% after four cycles. This consistent dropout is a difficulty that researchers face in almost every study. Reasons for this can be the insufficient rationale for QoL assessment in the protocol, lack of motivation by the investigators and also the lack of a dedicated staff member for QoL evaluation [36]. Our results concerning QoL are inconclusive and must be interpreted with caution. The sample size and the number of compliant assessments were too small and the dropout pattern indicates that patients who failed to answer are likely to have low QoL scores, which constitutes a bias. Nevertheless, the results give an indication of the QoL dimensions that could be considered for designing larger studies. These would focus on the changes of QoL scores over time and could concentrate on more sensitive dimensions: physical and role functioning, fatigue, dyspnea, insomnia and loss of appetite.

Some other studies have recently investigated the impact of chemotherapy on QoL in oesophageal cancer. Bamias et al. [37] treated 235 patients with epirubicin, cisplatin and protracted venous infusion of 5-FU for oesophagogastric adenocarcinoma. Seventy-four completed a baseline EORTC QLQ-C30 questionnaire. Physical and role functioning declined at 12 weeks, but pain was significantly decreased. No significant difference was detected between responders and non-responders. In a smaller study including 35 patients who received an irinotecan and cisplatin combination, QoL was assessed using FACT-G and EORTC QLQ-C30 [28]. Improvement in FACT-G global QoL score was observed in responders. These findings were primarily due to an improvement in emotional well-being scores and social/family well-being scores.

Attempts to refine the tools for measurement of QoL in patients with carcinoma of the oesophagus have resulted in a disease-specific module (EORTC QLQ-OES 24), which is designed to be used with the core questionnaire EORTC QLQ-C30 [38]. A large European study designed to test the reliability and validity of the EORTC QLQ-C30 and QLQ- OES 24 was recently completed. Future trials using palliative chemotherapy in patients with oesophageal cancer should aim to restore swallowing and to improve the QoL measured by disease-specific tools.

The essential conclusion of this study is that vinorelbine and cisplatin in combination constitutes an active regimen for patients with metastatic squamous cell carcinoma of the oesophagus with response rates similar to the better treatment in the previous EORTC randomised study (34% for vinorelbine–cisplatin compared with 35% for cisplatin–5-FU), while substantially reducing the level of fatal treatment-related toxicity. This 2-day regimen is also more convenient for patients than the 5-day cisplatin–5-FU combination. However, given the long duration of the trial and decline of the incidence of squamous cell oesophageal carcinoma in North America and some Western European countries, no further development of this combination is scheduled within the EORTC.


    Acknowledgements
 
We acknowledge Harry Bleiberg, Jean-Luc Raoul, Roberto Labianca, Catherine Vincent, Florence Lefresne-Soulas and Odile Guibon for their help in conducting this trial, and Stephen Johnson (Taunton and Somerset Hospital, Taunton, UK) for help in preparing the manuscript. Thanks also to Desmond Curran for performing the quality of life analysis for the ASCO meeting. This study was supported in part by Pierre Fabre Médicament, 45 place Abel Gance, 92654 Boulogne, France.


    Footnotes
 
+ Correspondence to: Dr T. Conroy, Department of Medical Oncology, Centre Alexis Vautrin, 54511 Vandoeuvre-lès-Nancy cedex, France. Tel: +33-3-83-59-84-60; Fax: +33-3-83-59-83-59; E-mail: t.conroy@nancy.fnclcc.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Faivre J, Forman D, Estève J et al. Survival of patients with oesophageal and gastric cancers in Europe. Eur J Cancer 1998; 34: 2167–2175.[ISI]

2. Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999; 26 (Suppl 5): 2–8.

3. Muller JM, Erasmi IT, Stelzner M et al. Surgical therapy of oesophageal carcinoma. Br J Surg 1990; 77: 845–857.[ISI][Medline]

4. Al-Sarraf M, Martz K, Herskovic A et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an Intergroup Study. J Clin Oncol 1999; 15: 277–284.[Abstract]

5. Enzinger PC, Ilson DH, Kelsen DP. Chemotherapy in esophageal cancer. Semin Oncol 1999; 26 (Suppl 15): 12–20.

6. Bleiberg H, Conroy T, Paillot B et al. Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer. Eur J Cancer 1997; 33: 1216–1220.[Medline]

7. Conroy T, Etienne P-L, Adenis A et al. Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. J Clin Oncol 1996; 14: 164–170.[Abstract]

8. Gebbia V, Caruso M, Valenza R et al. Vinorelbine plus cisplatinum for the treatment of stage IIIb and IV non-small cell lung cancer. Anticancer Res 1994; 14: 1247–1249.[ISI][Medline]

9. World Health Organisation. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organisation Offset Publication 1979; No. 28.

10. Hermanek P, Sobin HL. International Union Against Cancer (UICC). TNM Classification of Malignant Tumors. Berlin: Springer-Verlag 1987.

11. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10: 239–253.[ISI][Medline]

12. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[ISI][Medline]

13. Van Oosterom A. Tumor eligibility and response criteria for phase II and III studies and (sub) acute toxicity grading with suggested amendments to WHO criteria. In EORTC Data Center Procedures Manual, 2nd edition. EORTC 1992; pp. 119–133.

14. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

15. Loizou LA, Grigg D, Atkinson M et al. A prospective comparison of laser therapy and intubation in endoscopic palliation for malignant dysphagia. Gastroenterology 1991; 100: 1303–1310.[ISI][Medline]

16. Aaronson NK, Ahmedzai S, Bergman B et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376.[Abstract]

17. Fayers P, Aaronson N, Bjordal K et al. EORTC QLQ-C30 Scoring Manual. Brussels: EORTC 1995.

18. Fleming TR. One sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38: 143–151.[ISI][Medline]

19. Osoba D, Rodrigues G, Myles J et al. Interpreting the significance of changes in health-related quality of life scores. J Clin Oncol 1998; 16: 139–144.[Abstract]

20. Fayers P, Weeden S, Curran D. EORTC QLQ-C30 Reference Values. Brussels: EORTC Quality of Life Study Group 1998.

21. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 2000; 92: 205–216.[Abstract/Free Full Text]

22. Ajani JA, Ilson DH, Daugherty K et al. Activity of Taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 1994; 86: 1086–1091.[Abstract]

23. Macdonald JS, Jacobson JL, Ketchel SJ et al. A phase II trial of topotecan in esophageal carcinoma: a Southwest Oncology Group. Invest New Drugs 2000; 18: 199–202.[ISI][Medline]

24. Warner E, Jensen JL, Cripps C et al. Outpatient 5-fluorouracil, folinic acid and cisplatin in patients with advanced esophageal carcinoma. Acta Oncol 1999; 38: 255–259.[ISI][Medline]

25. Levard H, Pouliquen X, Hay JM et al. 5-Fluorouracil and cisplatin as palliative treatment of advanced oesophageal squamous cell carcinoma. A multicentre randomised controlled trial. Eur J Surg 1998; 164: 849–857.[ISI][Medline]

26. Ilson DH, Ajani J, Bhalla K et al. Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 1998; 16: 1826–1834.[Abstract]

27. Ilson DH, Forastiere A, Arquette M et al. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J 2000; 6: 316–323.

28. Ilson DH, Saltz L, Enzinger P et al. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 1999; 17: 3270–3275.[Abstract/Free Full Text]

29. Petrasch S, Welt A, Reinacher A et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer 1998; 78: 511–514.[ISI][Medline]

30. Kelsen DP, Ilson D, Wadleigh R et al. A phase II multi-center trial of paclitaxel (P) (Taxol) as a weekly one-hour infusion in advanced esophageal cancer (EC). Proc Am Soc Clin Oncol 2000; 19: 320a (Abstr 1266).

31. Slabber CF, Falkson CI, Musi NNM et al. A phase II study of docetaxel in advanced, inoperable squamous carcinoma of the esophagus. Proc Am Soc Clin Oncol 1999; 18: 300a (Abstr 1151).

32. Gebbia V, Mantovani G, Agostara B et al. Treatment of recurrent and/or metastatic squamous cell head and neck carcinoma with a combination of vinorelbine, cisplatin, and 5-fluorouracil: a multicenter phase II trial. Ann Oncol 1995; 6: 987–991.[Abstract]

33. Gebbia V, Mantovani G, Farris A et al. Vinorelbine, cisplatin and 5-fluorouracil as initial treatment for previously untreated, unresectable squamous carcinoma of the head and neck: results of a phase II multicenter study. Cancer 1997; 79: 1394–1400.[ISI][Medline]

34. Vicent JM, Garcia-Giron C, Feliu J et al. Phase II study of 5-fluorouracil (5-FU), cisplatin (CDDP) and vinorelbine (VNR) in patients (pts) with advanced adenocarcinoma of oesophagus. In Proceedings of the 9th International Congress on Anti-cancer Treatment, Paris, France, 1999. Abstract P183, p. 231.

35. Monnet I, Chariot P, Azli N et al. Severe mucositis after chemotherapy with vinorelbine, 5-fluorouracil, leucovorin and cisplatin. Eur J Cancer 1991; 27: 1716–1717.[ISI][Medline]

36. Fayers PM, Hopwood P, Harvey A et al. Quality of life assessment in clinical trials—guidelines and a checklist for protocol writers: the UK Medical Research Council Experience. Eur J Cancer 1997; 33: 20–28.[Medline]

37. Bamias A, Hill ME, Cunningham D et al. Epirubicin, cisplatin, and protracted venous infusion of 5-fluorouracil for esophagogastric adenocarcinoma. Response, toxicity, quality of life and survival. Cancer 1996; 77: 1978–1985.[ISI][Medline]

38. Blazeby JM, Alderson D, Winstone K et al. Development of an EORTC questionnaire module to be used in quality of life assessment for patients with oesophageal cancer. Eur J Cancer 1996; 32A: 1912–1917.