Infusion Of mitomycin-C Research Articles

Sequential intra-arterial infusion of 90Y-resin microspheres and mitomycin C in chemo refractory liver metastatic breast cancer patients: a single centre pilot study.

BackgroundThe aim of the study was to evaluate the safety and feasibility of intra-arterial mitomycin C (MMC) infusion after selective internal radiation therapy (SIRT) using Yttrium-90 (90Y) resin microspheres in liver metastatic breast cancer (LMBC) patients.Patients and methodsThe prospective pilot study included LMBC patients from 2012–2018. Patients first received infusion of 90Y resin microspheres, after 6–8 weeks response to treatment was assessed by MRI, 18F-FDG PET/CT and laboratory tests. After exclusion of progressive disease, MMC infusion was administrated 8 weeks later in different dose cohorts; A: 6 mg in 1 cycle, B: 12 mg in 2 cycles, C: 24 mg in 2 cycles and D: maximum of 72 mg in 6 cycles. In cohort D the response was evaluated after every 2 cycles and continued after exclusion of progressive disease. Adverse events (AE) were reported according to CTCAE version 5.0.ResultsSixteen patients received 90Y treatment. Four patients were excluded for MMC infusion, because of extra hepatic disease progression (n = 3) and clinical and biochemical instability (n = 1). That resulted in the following number of patient per cohort; A: 2, B: 1, C: 3 and D: 6. In 4 of the 12 patients (all cohort D) the maximum dose of MMC was adjusted due biochemical toxicities (n = 2) and progressive disease (n = 2). One grade 3 AE occurred after 90Y treatment consisting of a gastrointestinal ulcer whereby prolonged hospitalization was needed.ConclusionsSequential treatment of intra-arterial infusion of MMC after 90Y SIRT was feasible in 75% of the patients when MMC was administrated in different escalating dose cohorts. However, caution is needed to prevent reflux after 90Y SIRT in LMBC patients.

Intra-arterial Mitomycin C infusion in a large cohort of advanced liver metastatic breast cancer patients: safety, efficacy and factors influencing survival.

The aim of this study was to determine the safety and efficacy of Mitomycin C (MMC) infusion in a large cohort of advanced liver metastatic breast cancer patients (LMBC) and to determine factors influencing overall survival (OS). We retrospectively analysed LMBC patients, treated with MMC infusion between 2000 and 2017. Hepatic response was measured with baseline CT scans and first available CT scan after MMC infusion by RECIST 1.1 criteria. Adverse events were registered by the CTCAE version 5.0. OS and hepatic progression free survival (hPFS) were evaluated using Kaplan-Meier estimates. After univariable analysis, a stepwise forward multivariable (MV) prediction analysis was developed to select independent pre-treatment factors associated with OS. We included 176 patients with a total of 599 MMC infusions, mostly heavily pre-treated patients with a median time from diagnosis of MBC to MMC infusion of 36.9months. RECIST evaluation of liver lesions (n = 132) showed a partial response rate of 15%, stable disease of 43% and progressive disease in 17%. Adverse events grade 3 and 4 were reported in 17.5%. Median PFS was 5.5months and median OS was 7.8months. Significant independent baseline predictors of worse OS included number of prior systemic chemotherapy lines, prior liver ablation, higher liver tumour burden and elevated levels of bilirubin and ALT. MMC infusion is safe and effective in advanced LMBC patients. An increased number of prior therapies, a higher liver tumour burden and elevated levels of bilirubin and ALT were associated with a worse OS.

Phase I study of continuous mitomycin-C infusion in concomitant radiochemotherapy of primary inoperable advanced head and neck cancer

A phase I trial to evaluate the maximum tolerated dose (MTD) of continuous mitomycin-C infusion in radiochemotherapy of inoperable HNSCC. Twenty-one patients were treated with 70 Gy (2 Gy/day) and simultaneous chemotherapy (5-FU 600 mg/m2/day and MMC, both as continuous infusion on days 1-5 and 36-40. The MMC dose was dependent on dose escalation levels I-IV: 2/2.6/3.2/4 mg/m2/day. Dose limiting toxicity (DLT) (grade 3 mucositis and/or dysphagia) occurred at dose level IV (MMC 4 mg/m2/day). Accordingly, dose escalation level III (MMC 3.2 mg/m2/day) was set as the MTD. One and 2-year survival rate: 66.7 and 29.5%, disease free survival: 47.6 and 22.8%, respectively. Our study demonstrates that continuous infusion of 5-FU/MMC can be safely administered at a MMC dose of 3.21 mg/m2/day on days 1-5 and 36-40 in concomitant radiochemotherapy. A phase II study should be initiated to establish the role of this regimen in the treatment of head and neck cancer.

Concomitant radiochemotherapy in primary inoperable advanced head and neck cancer with 5-fluorouracil and mitomycin-C.

The purpose of this study was to evaluate the efficacy and toxicity of radiotherapy and concomitant 5-fluorouracil (5-FU) and mitomycin-C infusion in inoperable head and neck cancer. Seventy-six patients (86% men, 14% women), mean age 57 years, with primary inoperable head and neck cancer were treated with 70 Gy plus simultaneous intravenous chemotherapy with 5-FU (600 mg/m(2)/d, days 1 to 5) and mitomycin-C (10 mg/m(2), day 5 plus 36). After a mean follow-up of 13 months, 31 patients were alive. Complete response (CR) was seen in 63%. The 1- and 2-year overall survival rates were 67.7% and 39.5%, and locoregional control rates were 51.7% and 35.6%. Pretreatment hemoglobin <13.9 g/dL was associated with lower locoregional control rates (p = .03). Therapy was well tolerated (grade 3 mucositis in 21%, grade 4 in 1%, grade 3 leukopenia in 11%). Our radiochemotherapy regimen offers a curative option for this group of patients with a poor prognosis. Hemoglobin levels before therapy have an influence on prognosis.

Pharmacokinetic, angiographic, and histologic comparison of catheter-directed chemoembolization versus systemic chemotherapy in a canine model

Chemotherapy with selective intraarterial embolization may promote sustained contact of the drug with the tumor and thus could be more effective in the treatment. In this phenomenon, pharmacokinetics of a drug such as mitomycin C (MMC) play a significant role in guiding the therapy. Therefore, we have compared the pharmacokinetics of MMC and assessed angiographic, morphologic, and histologic changes in the kidney following intravenous MMC versus renal artery infusion with and without embolization with embolic agents, Rhizoma Bletillae (RB) and Gelfoam (GF). Dogs randomly divided into four groups underwent selective infusion protocols. Blood samples from renal and common iliac veins were analyzed for MMC levels. Angiography and pathology were performed at 4 days. Intravenous MMC (IV-MMC) caused significantly lower renal vein MMC levels than intraarterial MMC (IA-MMC) and GF + MMC. RB + MMC produced the lowest MMC levels in both veins (p < 0.05). Common iliac MMC levels were not significantly different after IV-MMC, IA-MMC, or GF + MMC. Angiographic and histologic studies showed extensive bleeding, necrosis, and vasculitis with thrombosis of the target kidneys after RB + MMC, GF + MMC, or IA-MMC, but not IV-MMC. Selective Rhizoma Bletillae chemoembolization can decrease systemic levels of MMC. Gelfoam does not provide sustained local release of MMC or decrease systemic levels of MMC compared with intravenous infusion. Selective renal MMC infusion without an effective embolic agent does not reduce systemic levels compared with intravenous delivery.

Pharmacokinetics of intraarterial mitomycin C in the chemoembolisation treatment of liver metastases

1. 1. The pharmacokinetics of mitomycin C (MMC) were investigated in 12 colorectal cancer patients with liver metastases undergoing chemoembolisation. Hepatic artery branches were embolized using polyvinylalcohol microspheres (150–250 μm) before applying 20 mg MMC in 4–8 min. 2. 2. Serum MMC concentrations were determined from peripheral venous blood samples by reversephase HPLC using ultraviolet detection. Pharmacokinetic parameters were computed assuming an open two-compartment model. 3. 3. Pharmacokinetic parameters were similar to values given in the literature for intravenous (IV) or intraarterial (IA) bolus MMC injections ( T max = 7.0 min following the beginning of MMC infusion, V ss=0.57 1/kg, C1=8.9 ml/min.kg, T 1 2 a = 8.3 min , T 1 2 β = 58.6 min ). 4. 4. The area under the serum concentration-time-curve (AUC), standardized by the MMC amount injected, was similar to values reported in the literature for IV or IA bolus injections. There is no evidence for reduced systemic MMC exposure following the embolization procedure used.

Pharmacokinetic, angiographic, and histologic comparison of catheter-directed chemoembolization versus systemic chemotherapy in a canine model

Chemotherapy with selective intraarterial embolization may promote sustained contact of the drug with the tumor and thus could be more effective in the treatment. In this phenomenon, pharmacokinetics of a drug such as mitomycin C (MMC) play a significant role in guiding the therapy. Therefore, we have compared the pharmacokinetics of MMC and assessed angiographic, morphologic, and histologic changes in the kidney following intravenous MMC versus renal artery infusion with and without embolization with embolic agents, Rhizoma Bletillae (RB) and Gelfoam (GF). Dogs randomly divided into four groups underwent selective infusion protocols. Blood samples from renal and common iliac veins were analyzed for MMC levels. Angiography and pathology were performed at 4 days. Intravenous MMC (IV-MMC) caused significantly lower renal vein MMC levels than intraarterial MMC (IA-MMC) and GF + MMC. RB + MMC produced the lowest MMC levels in both veins (p < 0.05). Common iliac MMC levels were not significantly different after IV-MMC, IA-MMC, or GF + MMC. Angiographic and histologic studies showed extensive bleeding, necrosis, and vasculitis with thrombosis of the target kidneys after RB + MMC, GF + MMC, or IA-MMC, but not IV-MMC. Selective Rhizoma Bletillae chemoembolization can decrease systemic levels of MMC. Gelfoam does not provide sustained local release of MMC or decrease systemic levels of MMC compared with intravenous infusion. Selective renal MMC infusion without an effective embolic agent does not reduce systemic levels compared with intravenous delivery.

Phase II-trial with 5-day continuous infusion of mitomycin-C in advanced inoperable NSCLC

Phase II-trial with 5-day continuous infusion of mitomycin-C in advanced inoperable NSCLC

Effect of intra-hepatoarterial infusion of MMC and CDDP for gastric cancer patients with liver metastases.

The influence of operative treatment and chemotherapy on the prognosis in 93 gastric cancer patients with liver metastasis was studied. Chemotherapy included the systemic administration of mitomycin C (MMC) (39 patients), an intra-hepatoarterial infusion of MMC (MMC IAC group) (19 patients) and an intra-hepatoarterial infusion of MMC and cisplatin (CDDP) (MMC + CDDP IAC group) (24 patients). Either MMC or MMC and CDDP were given in 1-4 courses every 3-4 weeks from the first one to two post operative weeks. The response rate was 4 per cent (1/23), 29 per cent (5/17) and 73 per cent (17/23) for MMC systemic administration, MMC IAC and MMC + CDDP IAC, respectively, with a significantly high rate of effectiveness for the MMC + CDDP IAC. In addition, regarding the median survival period, the MMC + CDDP IAC group showed 11.8 months, as compared with 2.9 months for other chemotherapeutic treatments, indicating a good prognosis regardless of any possible resection of the primary lesion. A Cox proportional hazard model revealed the treatment by MMC + CDDP IAC alone to be a significant independent factor. These results indicated that MMC + CDDP intra-arterial chemotherapy is an effective approach to gastric cancer with liver metastasis.

Preclinical Toxicity Study of Mitomycin C Infused into the Internal Carotid Artery of Beagle Dogs

Young adult male and female beagle dogs were infused with single doses of 0.5 (2 dogs) or 0.25 mg (5 dogs) Mitomycin C (MMC)/kg body weight directly into the internal carotid artery. Serial hematology and serum chemistry profiles, electrocardiograms and physical observations were made, the animals necropsied at varying times after dosage, and the major organs examined histologically. Results indicate that the dose limiting toxicity of this treatment regimen is myelosuppression. No ocular or neurologic toxicity was detected in any test animal. The findings suggest that infusion of MMC can be safely attempted in humans for the treatment of brain tumors that derive their blood supply from the internal carotid artery.

Pelvic intra-arterial mitomycin C infusion in previously treated patients with metastatic, unresectable, pelvic colorectal cancer and angiographic determination of tumor vascularity.

Thirty patients with unresectable pelvic tumors from recurrent or metastatic colorectal cancer, after failing all conventional chemotherapy or radiotherapy, were treated with mitomycin C (MMC) regional intra-arterial (IA) infusion. MMC at a dose of 20 mg/m2 in 100 mL of 5% dextrose in water was infused for a one-hour period through the regional artery (eg, hypogastric, gluteal) approached percutaneously via the femoral artery. This treatment was repeated every four to eight weeks. Of the 26 patients who could be evaluated, three had objective responses, 14 had tumor stabilization, and nine had no response. Median survival time for the responders (Rs) was 435 days, for stabilized patients (Ss) was 263 days, and for nonresponders (NRs) was 195 days, giving an overall survival time of 239 days. Fourteen patients (2 Rs, 8 Ss, and 4 NRs) had good relief of pain after the IA infusion. Thirty-three pelvic arteriograms (including three patients who had never received IA infusion) showed an avascular tumor of grade 0 in eight patients, a hypovascular tumor of grades 1 and 2 in 16 patients, and a vascular tumor of grade 3 in nine patients. Neovasculatures were mainly derived from the hypogastric artery or its branches (eg, gluteal, obturator, and pudendal artery), and occasionally were found to be derived from the superior hemorrhoidal, lumbar, and sacral arteries. The major side effect after the pelvic infusion was necrotizing cellulitis occurring in the buttock. Myelosuppression was manageable and other toxic effects were mild. Metastatic colorectal cancer occurring in the pelvis was basically a vascular-deficient tumor. Regional IA MMC infusion given intermittently was found effective in palliating pelvic pain and improving the quality of these patients' lives.

A phase I-II study of continuous 5-day infusion mitomycin-C

A phase I-II study was undertaken to establish the maximum-tolerated dose of a continuous 5-day infusion of mitomycin-C and its efficacy in patients with advanced metastatic drug-resistant breast and gastrointestinal malignancies. The dose-limiting toxicity was myelosuppression, predominantly thrombocytopenia, and was severe and cumulative. Nonhematologic toxicity was infrequent, and no renal or cardiac toxicity was seen. For patients with breast cancer who had received extensive prior therapy, 3 mg/m2/day for 5 days repeated every 6-8 weeks were well-tolerated doses; and for patients with gastrointestinal cancer, the maximum-tolerated dose was 4 mg/m2/day. One patient with breast cancer had a partial response lasting 4 months, and no responses were observed in patients with gastrointestinal cancer. The administration of mitomycin-C by continuous infusion did not appear to have improved its therapeutic index.

Bronchial angiography and intraarterial chemotherapy with mitomycin-C in bronchogenic carcinoma. Anatomy, technique, complications.

Bronchial angiography and intraarterial infusion of mitomycin-C were successfully performed in 39 of 47 patients with bronchogenic carcinoma. More than one course was given to several patients. No neurologic complications occurred and the side effects were insignificant. The pertinent anatomy of the bronchial and spinal arteries is summarized and a comprehensive description of the angiography and infusion technique is given. It is important that the infused artery is not occluded by the catheter and that the drug is properly diluted to avoid complications. The method appears to be of therapeutic value in the treatment of pulmonary carcinoma.

Preoperative infusion of mitomycin-C in the bronchial artery in squamous cell carcinoma of the lung.

Bronchial angiography was performed in 9 patients with squamous cell carcinoma of the lung. The tumor-feeding vessel was identified and infused with 10 mg of mitomycin-C (MMC) diluted in saline. At operation after 28 to 48 days complete remission of the tumor had occurred in 2 patients, almost complete in one, partial remission in 2 and a marked regression in 2. In 2 patients no change was noted. No side effects except moderate malaise and slight fever occurred.

Bronchial artery infusion of mitomycin-C in advanced bronchogenic carcinoma.

Bronchial angiography was performed in 17 patients with advanced non-oat cell bronchogenic carcinoma. The patients were treated 1 to 5 times with infusions of 10 mg of mitomycin-C (MMC) into the tumor-feeding bronchial artery. All but 2 patients received in addition small doses of vincristine (intravenously) and bleomycin (intramuscularly) or only bleomycin to potentiate the effect of MMC. No major side effects occurred and the systemic toxicity was insignificant. An objective tumor reponse was encountered in 11/17 patients. Intraarterial chemotherapy is strictly local and therefore effective especially in patients with limited or locally advanced disease. In patients with more extensive disease an adjunctive therapy of a more regional or systemic modality must be given.