Hypotonic Cisplatin Research Articles

Hypoxic Single-Pass Isolated Hepatic Perfusion of Hypotonic Cisplatin: Safety Study in the Pig

Isolated hepatic perfusion (IHP) of chemotherapy has been proposed to deliver high doses of drug while avoiding systemic toxicity. Hypotonic cisplatin has a high in vitro activity on human colon cancer cells. We studied the safety of a 30-min hypoxic single-pass IHP with hypotonic cisplatin. A preliminary in vitro assay was performed to compare the cytotoxicity of cisplatin and oxaliplatin, in either a normotonic or hypotonic medium. Cisplatin in hypotonic medium was then chosen for the in vivo IHP. Eleven pigs underwent 30 min of IHP with 0, 50, 75, or 100 mg/L of cisplatin in a hypotonic solution under total vascular exclusion of the liver. Clinical and biological parameters were recorded for 30 days, and liver histology was performed at necropsy. The cytotoxic activity of the effluent against resistant human colon cancer cells was tested in vitro. No hepatic failure was recorded after IHP with cisplatin, but limited foci of necrosis were found at necropsy in animals receiving 75 or 100 mg/L of cisplatin. No clinical, biological, macroscopic, or microscopic toxicity was observed after IHP with 50 mg/L of hypotonic cisplatin. The liver effluent showed high in vitro cytotoxic activity against colon cancer cells. A hypoxic single-pass isolated liver perfusion with hypotonic cisplatin is feasible and safe. Effluent from the liver is highly cytotoxic on cancer cells. A clinical study with 50 mg/L of hypotonic cisplatin is warranted in patients with unresectable liver metastases from colon cancer.

Recurrence Patterns in Patients With Early Stage Non-Small Cell Lung Cancers Undergoing Positive Pleural Lavage Cytology

Cytologic approaches such as pleural lavage cytology (PLC) are considered as possible aids to assessing prognosis of lung cancers. However, there is some controversy whether radical surgery is warranted based on the positive PLC findings with stage I non-small cell lung cancers (NSCLCs). From January 1991 to December 2002, PLC was performed before any manipulation or resection of the lung for 853 consecutive patients who had no macroscopic pleural effusion, dissemination, or diffuse adhesions and who subsequently underwent curative resection for NSCLCs. Results of PLC with reference to clinicopathologic characteristics, adjuvant therapy, 5-year survival, and recurrence patterns were analyzed. PLC findings were positive in 41 patients (4.8%), rates being most frequent with adenosquamous carcinomas and adenocarcinomas. In the positive group, distant metastases (72%) and pleural recurrence (25%) (p = 0.0011) were often observed, and the survival rate was significantly poorer (p < 0.002), even for patients with stage I disease (p = 0.009). As adjuvant therapies in the positive group after resection, 6 patients received hypotonic cisplatin and 15 received a distilled water infusion into the pleural space. Although only 2 patients had pleural recurrence, these therapies did not improve long-term outcome. PLC is a distinct prognostic factor for early stage lung carcinomas. Thus, we suggest that cytologic examination of PLC should be routine, even for patients with stage I NSCLCs before beginning lung resection. Moreover, curative resection, followed by adjuvant systemic therapy, could be necessary for improvement of outcome.

Intrapleural hypotonic cisplatin therapy appears effective for malignant pleural effusion in patients with non-small-cell lung cancer,

Intrapleural hypotonic cisplatin therapy appears effective for malignant pleural effusion in patients with non-small-cell lung cancer,

Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: a multi-institutional phase II trial

To assess the effect and toxicity of hypotonic cisplatin treatment (HPT) consisting of the intrapleural administration of cisplatin in distilled water for malignant pleural effusion in patients with non-small-cell lung cancer (NSCLC). Non-small-cell lung cancer patients with cytologically proven and previously untreated malignant pleural effusion were enrolled into this study. Firstly, the lung was fully re-expanded by a tube thoracostomy, and then 25 mg cisplatin in 500 ml of distilled water was instilled through a chest tube and then the tube was clamped. After 1 h, the tube was declamped and allowed to drain. The chest tube was removed when the pleural effusion volume decreased to 200 ml or less per day. A complete response (CR) was considered to occur when the pleural effusion disappeared. A partial response (PR) was determined to occur when the volume of pleural effusion remained under ¼ of hemithorax. The response at 4 weeks was evaluated by an extramural review. Out of 84 patients enrolled from February 1998 to August 2002, 80 patients were eligible and analysed in the present study. The toxicity of HPT was acceptable. Neither a haematological toxicity of any grade nor grade 4 nonhaematological toxicity was observed. Grade 3 nonhaematological toxicities were observed, including nausea (4%), vomiting (3%), pyothorax (1%) and dyspnoea (1%). The median time of drainage from HTP was 4 days. Twenty-seven (34%) and 39 (49%) patients achieved CR and PR, respectively, for an overall response rate of 83% (95% confidence interval, 74–91%). The median duration of the response was 206 days. The median survival time of all patients was 239 days. Hypotonic cisplatin treatment for malignant pleural effusion of NSCLC is therefore considered to be feasible and effective. A phase III study of HPT is thus warranted.

Phase III randomized controlled trial of hypotonic intraperitoneal cisplatin combined with oral UFT/PSK for the adjuvant treatment of gastric cancer invading the serosa

4027 Background: Peritoneal seeding is the most common pattern of recurrence in patients with gastric cancer invading the serosa who underwent curative gastrectomy. We developed hypotonic intraperitoneal cisplatin for preventing peritoneal recurrence in experimental models. Hypotonic cisplatin had a significant tumorcidal effect in vitro and in vivo. Hypotonic intraperitoneal cisplatin was tolerable in phase I clinical study. Now, we investigated the efficacy of the treatment in a multicenter prospective randomized controlled trial. Methods: 134 pts treated with curative resection for gastric cancer invading the serosa were randomized during surgery to one of 2 treatment arms. As per protocol, eligibility was confirmed by pathology and treatment course in 108 pts as follows: A -Hypotonic intraperitoneal cisplatin (100mg/m2) during surgery and systemic UFT (300mg/day) + PSK (protein-bound polysaccharide, 3g/day) (n=54) and B-Systemic UFT + PSK (n=48). Cisplatin diluted in 1,000 ml of warmed distilled water was injected to the abdominal cavity before closure of the abdomen. Drains were closed for 1 hour after injection of cisplatin. Results: Median follow up was 6.8 years. Postoperative complication rate and side effects were 21.3% and 30.8% in A-arm and 22.4% and 24.0% in B-arm. Tolerance was good in both arms. Peritoneal recurrence rate was 26.9% in A-arm and 40.0% in B-arm (chi-square p=0.16). Overall survival at 5 years was 62.0% and 31.0% in pts with or without hypotonic intraperitoneal cisplatin (log-rank p=0.03). Conclusions: Combining hypotonic intraperitoneal cisplatin and systemic oral chemotherapy improves the efficacy of oral chemotherapy after curative surgery for gastric cancer invading the serosa. No significant financial relationships to disclose.

Intrapleural Hypotonic Cisplatin Treatment for Malignant Pleural Mesothelioma: In Vitro Experiments and Clinical Application

We studied the inhibitory effects of hypotonic cisplatin on the growth of malignant pleural mesothelioma (MPM) cell lines in vitro, and assessed the effectiveness of intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy for patients with this tumor. In the in vitro experiments, mesothelioma cell lines were exposed to various concentrations of cisplatin in either saline solution or distilled water for up to 5 min. After 48 h incubation, we calculated the inhibition of cell growth. In the clinical study, five patients with MPM underwent intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy. The hypotonic cisplatin treatment inhibited cell growth at a significantly greater rate than the isotonic cisplatin treatment. Just 1-5 min exposure to 10 microg/ml of hypotonic cisplatin inhibited growth by more than 80%. Clinically, no recurrence was found in four of the five patients after a median follow-up period of 27 months (range: 16-36 months), although contralateral multiple pulmonary metastases were found in one patient 10 months after surgery. Hypotonic cisplatin treatment is effective against MPM, and should be investigated further.

P-677 Intrapleural hypotonic cisplatin treatment (HPT) for malignant pleural effusion in 80 patients with non-small cell lung cancer (NSCLC)

P-677 Intrapleural hypotonic cisplatin treatment (HPT) for malignant pleural effusion in 80 patients with non-small cell lung cancer (NSCLC)

Intraoperative intrapleural hypotonic cisplatin treatment for carcinomatous pleuritis.

We recently developed a new intraoperative intrapleural hypotonic cisplatin treatment for carcinomatous pleuritis found at thoracotomy in non-small cell lung cancer patients. In the present study, the efficacy and adverse events of this treatment as well as the pharmacokinetics of cisplatin in the blood after the treatment were evaluated. Twenty-one patients received the treatment for 15 minutes after completing the intrathoracic surgical procedures. The total and free platinum levels in the blood of five patients were then measured. As a control, 29 patients without such treatment were reviewed retrospectively. The survival rates in the treatment and non-treatment groups were similar. The pleural disease free survival of the treated patients was, however, significantly higher than that of the non-treated patients. Such pleural disease as effusion and the growth of the pleural disseminated tumors only appeared in three of the 21 (14%) treated patients while 26 of 29 (90%) non-treated patients had clinically detected pleural disease. The blood platinum levels after the treatment were extremely low and such low levels probably induced no systemic adverse events after the treatment. The only adverse event of this treatment was an increase in the postoperative drainage volume. These observations seem to suggest that intraoperative intrapleural hypotonic cisplatin treatment for carcinomatous pleuritis found at thoracotomy can, at least, delay the appearance of the pleural disease without any adverse events.

Hypotonic cisplatin treatment for carcinomatous pleuritis found at thoracotomy in patients with lung cancer: In vitro experiments and preliminary clinical results

We have developed an intraoperative intrapleural treatment with the use of distilled water combined with cisplatin for carcinomatous pleuritis found at thoracotomy in patients with non-small-cell lung cancer. In the in vitro experiment, three different cell lines were used as a model of malignant pleural effusion. Cell growth was examined after a 3-day culture, which was preceded by exposure of the cells to cisplatin in either phosphate-buffered saline solution or distilled water for 1/2 to 5 minutes. The growth inhibition of tumor cells after hypotonic cisplatin treatment was significantly greater than after treatment with saline solution and cisplatin. Tumor that was obtained by resection of non-small-cell lung cancer was used as a model to demonstrate decreased viability of the tumor after exposure to hypotonic cisplatin. The viability of the tumor in a 6-day culture, preceded by exposure to hypotonic cisplatin (50 micrograms/ml) for 10 minutes, was markedly decreased. Intraoperative intrapleural hypotonic cisplatin was instilled in seven patients with pleural carcinomatosis without side effects and with control of pleural dissemination and pleural effusion for 6 to 29 months.