Oxaliplatin for chemotherapeutic treatment and prevention of experimental peritoneal carcinomatosis in rats comparing the intraperitoneal and intravenous application mode.

BACKGROUND: The occurrence of peritoneal carcinomatosis after resection of colorectal carcinoma is still a major concern. In this study, we tested the cytostatic agent oxaliplatin delivered intraperitoneally and intravenously to prove whether it can significantly reduce intraperitoneal tumor growth. METHODS: Peritoneal tumor growth was experimentally induced with transfer of CC-531 colon cancer cells (5 x 10(6)) to the peritoneal surface of rats via laparotomy. Oxaliplatin was delivered either intraperitoneally or intravenously. In group A, oxaliplatin was administered directly after tumor cell transfer. While oxaliplatin was applied in group B on days 5, 10, and 15 after tumor cell implantation, in group C, it was administered on days 10, 15 and 20. The rats were sacrificed on day 30 after tumor cell transfer. Tumor weight, relative increase in tumor mass, volume of malignant ascites and the number of tumor nodes were determined. RESULTS: Oxaliplatin significantly inhibited tumor growth after direct (group A) and early postoperative application (group B) via the intraperitoneal route. The late postoperative administration of oxaliplatin (group C) did not cause a significant effect on peritoneal tumor growth as it did with the intravenous application mode in groups A, B, and C. CONCLUSIONS: In this experimental model, oxaliplatin was highly effective against intraperitoneal tumor spread but only with the intraperitoneal application route. Other cytostatic agents with different effector mechanisms should be combined with oxaliplatin to further increase the therapeutic efficacy of the favorable intraperitoneal treatment in subsequent studies testing, in addition, the effects on wound and anastomosis healing.

[Multimodal treatment of colon cancer?]. / Multimodale Therapie beim Kolonkarzinom?

Surgical therapy is still the basis of therapy of patients with colon carcinoma. Multimodal therapeutical concepts are presently applied as a therapeutical standard in the adjuvant therapy and increasingly in the systemic therapy of patients with primarily inoperable metastases of the liver to reach a secondary operability. Interdisciplinary multimodal therapeutical concepts are even accepted within the therapy of metastasized colon carcinomas. There are still unanswered questions regarding sequences of palliative systemic therapies and their combinations with local ablative methods.

Multicenter phase-I/II study using a combination of gemcitabine and docetaxel in metastasized and unresectable, locally advanced pancreatic carcinoma.

AIMS: To assess the maximum tolerability of a combined therapy regimen of gemcitabine and docetaxel, and to evaluate tumour response rate, survival time and tolerability in patients receiving these agents for advanced pancreatic carcinoma. PATIENTS AND METHODS: Patients (n=68) with pancreatic carcinoma (advanced and/or unresectable tumour growth or histopathologically diagnosed metastases) were enrolled in a multicenter phase-I (n=25) and phase-II study (n=43). Treatment during phase II of the study was continued until either complete tumour remission (CR), tumour progression, indicated clinically or by means of radiological imaging, or until unacceptable toxicity occurred. RESULTS: Phase I: the tolerability maximum of the combined agents was established at gemcitabine 1000 mg/m(2) and docetaxel 35 mg/m(2) with tolerable adverse events. Phase II: a total of 139 chemotherapy cycles were completed (mean, 3.2; range, 1-10). While CR was achieved in three of 43 patients (7%), in five further cases, partial remission (PR) was documented, amounting to an overall response rate (OR) of 18.6%. Eighteen patients showed stable disease (41.9%), whereas in 17 of 43 subjects (39.5%), primary tumour progression was detected. The median survival time was 9.0 months; the 1-year survival rate was 13.9% (six of 43 patients). These results were associated with a side-effect profile of moderate severity and acceptable quality of life (QOL). CONCLUSION: The combination of gemcitabine and docetaxel for chemotherapy in unresectable pancreatic carcinoma was well tolerated. Survival time and 1-year survival rate proved promising and the regimen appears suitable for further evaluation in a prospective phase-III study setting.

Phase I trial using weekly administration of gemcitabine and docetaxel in patients with advanced pancreatic carcinoma.

BACKGROUND: In advanced pancreatic carcinoma, no effective chemotherapy has been found yet due to the lack of appropriate response. The frequent use of gemcitabine is based on the fact that there is a significant improvement in the quality of life, but neither an effect on remission nor a detectable increase in survival rates could be observed. Therefore, the hypothesis was that the combination of gemcitabine with other drugs can result in a better outcome of patients. The aim of this study was to determine the maximally tolerable dosage of gemcitabine and docetaxel using a weekly administration regimen. PATIENTS AND METHODS: Twenty-five patients with advanced or metastatic pancreatic carcinoma received combination chemotherapy using gemcitabine and docetaxel in a weekly administration regimen, beginning with 800 mg/m2 of gemcitabine and 25 mg/m2 of docetaxel. Four patients were originally enrolled for each of the seven different dosages of both drugs. Side effects were assessed according to the WHO standard. Quality of life was evaluated according to the Core Quality of Life Questionnaire (QLQ-C30) of the European Organization for Research and Treatment of Cancer. RESULTS: Using the two maximal dosages of gemcitabine and docetaxel (gemcitabine, 800 and 1,000 mg/m2, and docetaxel, 45 and 40 mg/m2; respectively), only 3 and 2 patients were enrolled, respectively, because of toxic side effects > or = grade III according to WHO grading. Maximal dosages with tolerable side effects were 1,000 mg/m2 of gemcitabine and 35 mg/m2 of docetaxel given in weekly intervals. Main side effects of this combination chemotherapy were gastrointestinal symptoms and hematologic toxicity. CONCLUSION: Combination therapy with gemcitabine and docetaxel in advanced or metastatic pancreatic carcinoma is a well-tolerated and acceptable alternative treatment option with regard to the severity of side effects and its positive impact on quality of life and tumor-associated pain. According to the study endpoint, dosages of 1,000 mg/m2 of gemcitabine and 35 mg/m2 of docetaxel are recommended as maximum-tolerated doses (given in weekly intervals) for a future phase II trial.

[Five cytostatic substances in animal studies for prevention and treatment of experimentally induced peritoneal carcinomatosis]. / Fünf Chemotherapeutika in tierexperimentellen Untersuchungen zur Prävention und Therapie der Peritonealkarzinose.

High local recurrence rates within the previous tumor bed or at the peritoneum remain an unsolved problem after surgical resection of malignant gastrointestinal tumors such as gastric, colorectal or pancreatic carcinoma. Currently, there are no standardized treatment protocols available for the prevention or treatment of peritoneal carcinomatosis. In a basic experimental trial, mitomycin, cisplatin, 5-FU, oxaliplatin and CPT-11 were used to prevent or treat peritoneal carcinomatosis induced in rats. Experiments were performed in three groups (n = 8 each) of animals plus two control groups. In the first group, Mitomycin, Cisplatin, 5-FU, Oxaliplatin and CPT-11 (n = 24 each) were applied directly following tumor cell implantation into the peritoneal cavity. In the second group, early postoperative intraperitoneal (i. p.) chemotherapy (day [d] 5, 10, 15 following surgical intervention for tumor cell transfer) was administered, whereas in the third group, late i. p. chemotherapy (d 15, 20, 25 following surgery) was given via a port-a-cath aiming for significant reduction of a visible, already established peritoneal carcinomatosis. Mitomycin and cisplatin were highly effective to prevent peritoneal carcinomatosis (direct application immediately after tumor cell transfer - 1 (st) treatment group). Using early postoperative i. p. chemotherapy (2 (nd) group), 5-FU and CPT-11 were shown to be significantly effective to reduce the intraperitoneal tumor spread. None of the cytostatic agents was able to decrease significantly an already generated peritoneal carcinomatosis (3 (rd) treatment group). The results suggest that novel chemotherapeutic drugs should be proven for their potential to alter peritoneal metastases of GI tumors i) in comparison with established drugs and ii) depending on the application time and mode.

Prevention and treatment of peritoneal carcinomatosis in experimental investigations with CPT-11 and oxaliplatin.

Following surgical resection of colorectal carcinoma, local recurrence in the tumor bed or in the mesentery remains a frequently encountered problem. Currently there are no recognized standard therapy protocols for the prevention of local recurrence or the treatment of peritoneal carcinomatosis. The aim of our trial was to investigate whether CPT-11 and oxaliplatin could decrease i.p. tumor growth in a basic experimental animal model. Experiments were performed on three groups of animals plus controls. In the first group, the cytostatic agents were applied directly following tumor cell implantation into the peritoneal cavity. In the second group, early postoperative i.p. chemotherapy (days 5, 10 and 15 following surgery) was administered. In the third group, late i.p. chemotherapy (days 15, 20 and 25 after tumor cell transfer) was administered with the intention of reducing a manifest peritoneal carcinomatosis. The trial also set out to describe any side effects observed following i.p. administration. The results indicated that CPT-11 and oxaliplatin were highly effective in reducing i.p. tumor spread after direct i.p intraoperative application. Intraperitoneal administration of CPT-11 or oxaliplatin also decreased i.p. tumor growth after early i.p. chemotherapy. CPT-11 was a little more effective with lower side effects. However, it was clear that it was not possible to treat a manifest peritoneal carcinomatosis in this way.

Prophylaxis of peritoneal carcinomatosis in experimental investigations.

BACKGROUND AND AIMS: We compared the effectiveness and side effects of various cytostatic agents for use in perioperative intraperitoneal irrigation to prevent peritoneal carcinomatosis. METHODS: The adenocarcinoma cell line CC-531 was implanted during laparotomy at the mesenterial trunk of anesthetized male WAG rats. Direct perioperative intraperitoneal chemotherapy was performed after 5 min with either 5-fluorouracil, cisplatin, or mitomycin; controls received only tumor cells. The animals were inspected daily over 30 days for side effects. They were then killed, and the greater omentum and mesentery were resected, the tumor mass was examined for the presence of peritoneal carcinomatosis, and tumor nodules in the greater omentum and mesentery were counted. RESULTS: All the animals in the control group developed histologically confirmed peritoneal carcinomatosis. Animals receiving cisplatin or mitomycin by direct intraperitoneal perioperative chemotherapy showed no macroscopic or histological evidence of tumor growth. Two animals in the fluorouracil group had macroscopically and histologically manifest tumor growth; another animal showed only histological evidence of malignancy. Substantial side effects were noted in the cisplatin group, with all animals experiencing bleeding in the peritoneum and toxic necrotic reactions of the colon; two animals died of these side effects. CONCLUSION: Direct intraperitoneal chemotherapy with cisplatin or mitomycin prevents peritoneal carcinomatosis in experimental investigations.