1 Department of Medical Oncology, VU Medical Centre, Amsterdam; 2 Department of Internal Medicine, De Heel-Zaans Medisch Centrum, Zaandam, The Netherlands
Received 5 July 2003; revised 28 September 2003; accepted 6 October 2003;
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ABSTRACT |
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For oesophageal cancer there is no effective standard therapy. We studied the feasibility and efficacy of the cisplatingemcitabine combination chemotherapy in patients with unresectable oesophageal cancer.
Patients and methods:
Thirty-six chemonaïve patients with unresectable or metastatic oesophageal adenocarcinoma (24) or squamous-cell-carcinoma (12) were treated with cisplatin (50 mg/m2, days 1 and 8), followed by gemcitabine (800 mg/m2, days 2, 9 and 16), every 28 days. Feasibility and efficacy were studied.
Results:
Toxicity was substantial but manageable. A median number of four therapy cycles was given. The most frequent grade 3 toxicities were leukopenia (75%) and neutropenia (83%). Three patients developed neutropenic fever. Grade 3/4 thrombocytopenia occurred in 24 out of 36 patients (67%), but did not result in serious bleeding disorders. Myelotoxicity was cumulative and required omission of gemcitabine on day 16 in 63% of cycles. Anaemia required treatment with erythropoietin, red blood cells or both in 81% of patients. Non-haematological toxicity consisted mainly of grade 1/2 nausea/vomiting or fatigue. Fourteen out of 34 evaluable patients had a major objective response (41%; two complete and 12 partial responses). The median actuarial survival was 9.8 months.
Conclusion:
This cisplatingemcitabine regimen was feasible, with myelosupression being the main toxicity, and had significant activity in patients with advanced oesophageal cancer.
Key words: adenocarcinoma, advanced oesophageal cancer, cisplatin, gemcitabine, phase II, squamous cell carcinoma
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Introduction |
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These poor results underscore the need to identify new agents in the treatment of oesophageal cancer. Gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analogue, is attractive for combination chemotherapy due to its activity in various solid tumours and mild toxicity profile. Gemcitabine acts by incorporation of its triphosphate (dFdCTP) into DNA, subsequently leading to inhibition of DNA replication and repair. Several self-potentiating mechanisms have been described [1012], enhancing the incorporation of dFdCTP into DNA and possibly also into RNA.
Preclinical studies showed schedule-dependent additive and synergistic interactions between cisplatin and gemcitabine [1315]. Cisplatingemcitabine combination chemotherapy is recognized as an active treatment in various solid tumours [12]. In oesophageal cancer this combination has not been studied previously. Based on results of our schedule finding phase I/II study, comparing four alternating sequences with a 4- and 24-h interval of cisplatin and gemcitabine, the schedule with cisplatin (50 mg/m2, days 1 and 8) followed after 24 h by gemcitabine (800 mg/m2, days 2, 9 and 16) was chosen for phase II evaluation [16, 17].
The aim of this study was to determine the efficacy and toxicity of patients with metastatic or unresectable oesophageal cancer treated with cisplatin and gemcitabine.
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Patients and methods |
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Pretreatment evaluation included medical history and clinical examination. In addition, haematology and blood chemistry tests, urinanalysis, electrocardiogram and chest radiograph were performed. Pretreatment staging consisted of computed tomography (CT) of the chest and abdomen. Before each treatment cycle, a complete blood count and chemistries were repeated. Complete blood cell counts and serum creatinine were measured weekly. Repeat radiographic studies were performed every other cycle.
Study design and drugs
Cisplatin 50 mg/m2 was administered as a 1 h infusion on days 1 and 8, and gemcitabine (Gemzar®; 2',2'-difluoro-2'-deoxycytidine) 800 mg/m2 over 30 min weekly on days 2, 9 (24 h after cisplatin) and 16 on a 4-weekly schedule. Before cisplatin, patients received i.v. hydration with 1000 ml normal saline plus 20 mmol potassium chloride and 2 g magnesium sulfate over 2 h. After cisplatin infusion, 4000 ml normal saline plus 80 mmol potassium chloride and 8 g magnesium sulfate were given over 24 h. Prophylactic antiemetics, 8 mg ondansetron and 8 mg dexamethasone, were administered twice on the day of cisplatin infusion. No prophylactic use of granulocyte colony-stimulating factor (G-CSF) was planned.
Toxicity was evaluated before each course and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 2.0). Treatment was delayed if grade 3 WBC toxicity and/or grade
2 thrombocytopenia occurred. If blood counts did not permit gemcitabine administration on day 16, this was omitted. If treatment delay was >2 weeks, the patient went off study. Dose modifications were not applied for both gemcitabine and cisplatin. Treatment was discontinued for disease progression, unacceptable toxicity or the patients wish to stop the treatment. Six cycles were given to responding patients, and patients with stable disease when feasible.
Response to therapy was assessed, according to the WHO criteria, every two courses. To qualify for response analysis, patients had to complete at least one cycle of treatment. Duration of response was defined as time from documentation of the response to documentation of disease progression. Time to progression (TTP) was defined as time from start of treatment to documentation of disease progression. Survival was defined as time from start of treatment until death.
Toxicity analysis and statistics
The primary end point of the study was response rate. The study was designed using the Gehan design [18]. Assuming a response rate of at least 20%, initially 14 patients were accrued. If the response rate was at least 20%, then the probability of obtaining no responses in 14 patients is <0.05. Accrual was planned for a total of 35 patients.
Correlations were determined using the Pearson or Spearman analysis for normal and non-parametric data, respectively. The computer program SPSS (Version 7.5; SPSS Inc., Chicago, IL) was used for statistical analysis.
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Results |
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Toxicity
All patients were evaluable for toxicity. Toxicity was manageable and no treatment-related deaths were observed. Myelosuppression was the most important toxicity. Table 2 lists the haematological toxicity of the first two and of all delivered treatment cycles. Over all cycles, grade 3 or 4 thrombocytopenia was observed in 24 out of 36 patients (67%). No serious bleeding disorders occurred due to thrombocytopenia. Four patients with platelets <10 x 109/l received a platelet transfusion. One patient had a bleeding gastric ulcer requiring surgery without thrombocytopenia, which was therefore probably not treatment related. Over all cycles, grade 3 and 4 leukopenia was observed in 27 out of 36 patients (75%) and neutropenia in 24 out of 29 (83%) evaluable patients. The neutrophils were not always measured on day 15 and were therefore evaluable in a lower number of patients. Three patients received secondary G-CSF after two (two patients) or four (one patient) cycles. Neutropenic fever was observed in three patients. Anaemia occurred commonly and required treatment with erythropoietin, red blood cells or both in 81% of patients. Myelotoxicity [mean ± standard error of the mean (SEM)] was cumulative for both platelets (Figure 1A), with day 15 values decreasing from 122 ± 19 in the first cycle to 52 ± 8 in the fourth cycle (P = 0.0001), and for WBCs (Figure 1B) with nadir values from 2.9 ± 0.6 in the first cycle to 2.4 ± 0.2 in the fourth cycle (P = 0.22).
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Response
Fourteen out of 34 evaluable patients responded (41%; 95% confidence interval 25% to 59%), including two complete responses and 12 partial responses. One additional patient also responded; however this was not confirmed after 4 weeks due to the patients wish to stop treatment. Stable disease was seen in 17 patients and three patients had progressive disease. Responses were observed in five out of 12 patients with SCC (42%) and nine out of 22 patients with adenocarcinoma (41%). Responses were obtained in both metastatic (13/26) and locally advanced disease (1/3). The response by disease site was as follows: primary tumor, 14 patients (all responders); lymph nodes, 11; liver metastasis, five; lung metastasis, two; and ascites, one. The median response duration and time to progression were 5.5 and 6 months, respectively. Responses were seen after a median of two cycles (ranging from one to four cycles).
One complete remission was obtained in a patient with an adenocarcinoma metastasised to the liver. CR was determined by CT, repeated endoscopy and positron emission tomography. The other patient had a T3N1M1 SCC with a positive lymph node at the truncus coeliacus. After two and four cycles, no tumour could be observed by CT or endoscopy, however an endoscopic biopsy of the lymph node at the truncus coeliacus was still positive. Three more patients underwent surgery after chemotherapy. The first patient with a partial response was radically resected, while for the second and third patients, both with stable disease (minor responses), an oesophagectomy was not possible due to locally advanced disease and an abscess in the operation area, respectively. Survival was determined by KaplanMeier analysis and is depicted in Figure 2. The median actuarial survival was 9.8 months, ranging from 3 to 28 months, with five patients alive after a median follow-up of 11 months.
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Discussion |
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The epidemiology of oesophageal cancer has changed over the past two decades. Adenocarcinomas are currently the predominant subtype of oesophageal cancer, with a 67% incidence in the current study [1, 24]. Response rates and median survivals for patients with adenocarcinoma and SCC were comparable, in accordance with previous studies [22, 23].
Although gemcitabine administered as a single agent did not show activity in metastatic oesophageal cancer [25], we observed encouraging results for the combination with cisplatin. The activity of the combination might be explained by the synergistic interactions between gemcitabine and cisplatin [1214]. Cisplatin increased gemcitabine incorporation in DNA, as well as DNA strand break formation induced in a gemcitabine-resistant cell line [14]. In addition, gemcitabine also increased the formation of Pt-DNA adducts and decreased the repair of Pt-DNA adducts in a cisplatin-resistant cell line.
There is no clear evidence for the best sequence of administration of the two drugs. Preclinical studies indicated a small advantage in administering the gemcitabine prior to the cisplatin [13, 26]. However, a pharmacological schedule-finding study with cisplatin administered 24 h prior to gemcitabine produced the best pharmacological profile [16], but resulted in more severe leukopenia [17]. In that study we also observed several responses in oesophageal cancer. Based on the pharmacokinetics, we decided to investigate further the cisplatin-preceding-gemcitabine regimen, in contrast to previous clinical studies using the alternative schedule.
Dysphagia is one of the most common symptoms of esophageal cancer. Many of our patients had dysphagia at the start of therapy, and in case of serious dysphagia a stent was placed. We did not consequently record the reponse of dysphagia on therapy, but in general relief of dysphagia seemed to occur in the responding patients after one to four cycles of chemotherapy.
Toxicity was substantial but manageable. There were no treatment-related deaths and only three patients had febrile neutropenia. Toxicity was mainly haematological, with the nadir seen at day 16, as expected [17]. Omissions of gemcitabine administration on day 16 due to myelotoxicity were necessary in 63% of administered cycles. This toxicity profile might be improved by using a 3-weekly schedule. In non-small-cell lung carcinoma, the 3-weekly schedule with gemcitabine administered prior to cisplatin showed good activity and was well tolerated [27, 28].
The development of effective systemic therapy is also a high priority for patients with locally advanced oesophageal cancer eligible for treatment with curative intent. Relative small gains in advanced disease may translate into remarkable improvement in more localized disease. Based on the activity of the gemcitabinecisplatin combination in advanced oesophageal cancer, we are currently studying the combination as part of combined modality therapy in patients with locally advanced oesophageal cancer.
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Acknowledgements |
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FOOTNOTES |
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