A case of small-cell esophageal cancer with chronic renal failure undergoing hemodialysis safely treated with cisplatin and etoposide

After the fourth course was finished, the lesion was evaluated. A partial response was noted, and the patient was able to eat solid food after the treatment. Esophagography showed that the tumor was reduced to 4 cm and had become flatter (Fig. 3a). Esophageal endoscopy revealed that the tumor which projected into the lumen had almost disappeared. Only a mildly irregular mucosa and a minute elevated mass remained in the cervical esophagus, 22–24 cm from his incisors (Fig. 3b). A CT scan showed a solid mass which had decreased to 21 mm in size, in the cervical esophagus, which did not seem to invade the trachea. The size of the lymph node swelling had also decreased (Fig. 3c). The serum level of Pro-GRP fell after the course of chemotherapy and rose after the interval between chemotherapy. The minimum value of pro-GRP was 38.5 pg/ml, but after 4 courses of this regimen, the serum level of Pro-GRP was 165.7 pg/ml. An additional 5 courses of treatment were administered. At that time, examinations had shown no progressive growth of the tumor. However, 12 months after the initial treatment disease progression was observed. The CT scans showed regrowth of the main tumor and multiple cervical lymph node metastases. Because the patient’s pain had worsened because of enlargement of the lymph node metastases, and his performance status had abruptly worsened, palliative radiation (30 Gy) was administered for the purpose of pain relief. However, because the patient could not eat and was markedly emaciated, we judged that the continuation of the treatment would be difficult, so best supportive care was provided. One month after stopping treatment, his body weight continued to decrease, and marked general edema occurred. The patient died as a result of disease progression.

With regard to the toxicity of this chemotherapy regimen, the patient complained of only mild nausea and loss of appetite (Grade 1 by NCI-CTCAE v4.0). Although occasional afebrile neutrocytopenia (Grade 3) was apparent from the blood chemistry data, we were easily able to treat it with granulocyte colony stimulating factor (G-CSF). The patient had nephrogenic anemia (hemoglobin 7.2 g/dl, packed cell volume 23.0%) just before chemotherapy, and so experienced exacerbation of his anemia (Grade 4) as a result of the chemotherapy. Therefore, a blood transfusion was performed twice during the course of treatment. These complications were tolerable.

We measured plasma levels of total CDDP (t-CDDP) and VP-16. Venous blood samples were collected into tubes just before and after drug administration, then 0.5, 1, 2, 3, 4, 5, 12 h, 1 (24 h), 2, 3, 4 days, and 1, 2, 3 weeks after administration. After separating plasma from each sample, the concentrations of t-CDDP and VP-16 were measured in a portion of the plasma. As shown in Figs. 4 and 5, we compared the time–concentration curves of t-CDDP and VP-16 between the patient with renal insufficiency and those with normal renal function. Figures 4b and 5b were provided by Dr Masumi Sawada and Dr Akira Wakui, respectively. The pharmacokinetic parameters, including half-life (t _1/2) and area under the curve (AUC), were calculated for CDDP and VP-16.

The t-CDDP concentration decreased abruptly immediately after administration of CDDP (αphase); afterward it decreased more slowly (βphase) (Fig. 4a). This biphasic pattern of the pharmacokinetics was similar to that for patients with normal renal function (in a phase 1 clinical trial) [3] (Fig. 4b). The t-CDDP concentration on initiation of hemodialysis was 2.31 μg/ml. The maximum drug concentration (C _max) (CDDP 50 mg/body) as shown in Fig. 4b was higher than that observed in our data (CDDP 120 mg/body). However, in other studies, it was reported that the C _max was 1.40, 0.98, 1.07 μg/ml (CDDP 80 mg/body) [4], 3.31 μg/ml (CDDP 80 mg/m²) [5], and 2.90 μg/ml (CDDP 100 mg/m²) [6]. The reason why the value of C _max in a phase 1 clinical trial tends to be high is unclear. However, our data were consistent with those in previous reports. It decreased to 1.39 μg/ml at 0.5 h, and was 1.56 μg/ml 4 h after the initiation. Most t-CDDP was removed in the first 30 min of dialysis. The lower limit of detection of t-CDDP was 0.1 μg/ml. The maximum t-CDDP concentration was 2.31 μg/ml, and it had decreased to 0.17 μg/ml 28 days after the administration of CDDP. CDDP remained in the plasma for at least 28 days, but the last concentration approached the lower limit of detection. We also measured the plasma levels of t-CDDP in the first and second courses and compared each point in both courses. The t-CDDP concentrations in the second course were significantly higher than those in the first course (Wilcoxon t test, P < 0.01), indicating a cumulative effect of CDDP in this regimen. The t _1/2α was 0.036 h, and t _1/2β was 119 h for the first course of CDDP. In contrast, the t _1/2α was 0.411 h and t _1/2β was 164 h for the second course. The AUC was 265 and 363 μg h/ml in the first and second courses, respectively. The t _1/2 was extended and the AUC was increased in the second course in comparison with the first course. Many reports have described that the t _1/2β was approximately 100 h in patients with normal renal function [6], and Tokunaga et al. [4] reported that the t _1/2α for CDDP was 0.53 ± 0.07 h, t _1/2β was 94.2 ± 11.6 h, and AUC was 71.3 ± 6.26 μg h/ml after administration of 90.8 ± 6.34 mg to patients with normal renal function. In this case, we obtained a similar t _1/2 value, but the AUC tended to be greater than for patients with normal renal function.

The VP-16 maximum concentrations were 9.96, 10.44, and 10.45 μg/ml after the three administrations and rapidly decreased to 5.06, 6.07, and 5.76 μg/ml 4 h after administration (αphase). The concentrations then decreased gradually (βphase) (Fig. 5a). The pharmacokinetics had a biphasic pattern which was also comparable with the curves for patients with normal renal function (in a phase 1 clinical trial) [7] (Fig. 5b). The concentration had decreased to 1.45 μg/ml at 24 h and 0.62 μg/ml at 48 h after administration, which was approaching the lower limit of detection. Almost all of the VP-16 in the plasma was excreted within 48 h. Comparison of each point after the first and second administrations revealed the VP-16 concentrations were not significantly different (Wilcoxon t test, P = 0.068), and no significant cumulative effect caused by the alternate-day administration for 3 days was apparent. We also evaluated the pharmacokinetic parameters of VP-16 in this patient. The t _1/2α was 2.31 h and t _1/2β was 17.2 h after the first administration in the first course of treatment, and the t _1/2α was 3.10 h and t _1/2β was 16.9 h after the second administration during the first course. The AUC values were 128 and 139 μg h/ml, respectively, after the first and second administrations during the first course. There was little difference between t _1/2 and AUC after the first and second administrations. On the other hand, Wakui et al. [7] reported that the t _1/2α was 0.13 and 0.30 h, t _1/2β was 4.85 and 4.01 h, and the AUC was 95.7 and 94.8 μg h/ml, respectively, after the administration of 120 mg/m² in patients with normal renal function (based on a phase 1 clinical trial). This suggested that there was a tendency for both the t _1/2 and AUC to increase in this dialysis patient in comparison with patients with normal renal function.