Intensity-modulated radiotherapy improves survival and reduces treatment time in squamous cell carcinoma of the anus: A National Cancer Data Base study.

BACKGROUND: Chemoradiation with 5-fluorouracil and mitomycin remains the standard of care for squamous cell carcinoma (SCC) of the anal canal. A prolonged treatment time is associated with inferior disease-specific outcomes. Radiation Therapy Oncology Group trial 0529 demonstrated decreased toxicity and fewer treatment breaks with intensity-modulated radiotherapy (IMRT), but this has not been assessed in a randomized trial. Using data from the National Cancer Data Base (NCDB), this study evaluated the impact of IMRT on treatment time and survival in anal SCC. METHODS: The NCDB was used to identify patients with anal cancer from 2004 to 2013. The included patients were those with stage I to III squamous cell cancer of the anal canal who had received definitive chemoradiation by IMRT or 3-dimensional conformal radiation therapy (3DCRT). Statistical analyses were performed with logistic regression, Kaplan-Meier analysis, Cox proportional hazards analysis, and propensity score-matched analysis. RESULTS: Of 6814 patients, 57.4% were treated with 3DCRT, whereas 42.6% received IMRT. Patients receiving IMRT had a reduced risk of a long treatment time in a multivariate analysis (P < .001). The 5-year overall survival (OS) rates with IMRT and 3DCRT were 80.8% and 78.9%, respectively (P = .0036). According to a propensity analysis, patients receiving IMRT had improved OS (P = .039) and a reduced risk of a long treatment time (P < .0001) in a multivariate analysis. CONCLUSIONS: IMRT use was associated with significantly reduced overall treatment time and improved survival in comparison with 3DCRT. It is important to note that NCDB data are not as robust as randomized data. However, these results further support the use of IMRT as part of sphincter-preserving therapy for the anal canal.

Penetration of mitomycin C in human bladder.

The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical dose of MMC (20 mg/40 ml) was instilled and maintained in the bladder for 60 to 120 min at which time the solution was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tissues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patients had a low final MMC concentration in urine (< 66 micrograms/ml) or had the MMC solution drained more than 30 min before ligation of the blood vessels. Among these 17 patients, the concentration in the urothelium was measurable in only 4 patients, while the concentrations in deeper tissues were not measurable. In the remaining 7 patients where the urine concentration was > 120 micrograms/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall contained significant MMC concentrations. The drug penetration was studied in the latter 7 patients, using sections of bladder wall that were grossly normal and non-tumor bearing. Concentrations in the bladder wall declined semilogarithmically with tissue depth from the urothelium to the deep muscle and reached a plateau at about 2000 microns depth. The median MMC concentrations were 5.6 micrograms/g in the urothelium and lamina propria interface, 2.7 micrograms/g in the lamina propria, and 0.9 microgram/g in the muscularis. The distance over which the MMC concentration decreased by one-half was about 500 microns. The concentration ratio between the urine and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentration in urine, urothelium, and the averaged bladder tissue concentrations, respectively. Paired superficial tumor and normal tissues were obtained from 5 bladders. In 4 of 5 cases, the concentration in tumors was higher than in normal tissues, while the reverse was seen in the remaining tumor. In one sessile bladder tumor a complete concentration-depth profile could be obtained. While the concentrations in the tumor tissue were 2-3-fold higher than that in the adjacent normal tissue, the rate of concentration declined with respect to tissue depth and hence the distance over which the MMC concentration decreased by one-half was similar in both tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients.

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)

Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine.

The design of an ongoing Phase III study of intravesical mitomycin C therapy to treat bladder cancer is partly based on the assumption that drug penetration into bladder tissue is linearly related to drug concentration. The present study was designed to (a) test this assumption and (b) to compare drug concentrations in tumor and adjacent normal tissues in human bladders. We previously reported the uptake kinetics of a 20-mg dose in dog and human bladders (M. G. Wientjes et al., Cancer Res., 51: 4347-4354, 1991, and Cancer Res., 53: 3314-3320, 1993). The present study used a 40 mg/20 ml dose. Serial blood and urine samples were taken from dogs during the 120-min instillation. Bladder tissues were harvested from dogs and patients at the end of instillation. A comparison of the results of the present and previous studies indicates identical tissue penetration kinetic parameters in dogs for the two doses, i.e., a approximately 30-fold concentration drop across the urothelium and a half-width of approximately 500 microns. In addition, the average tissue concentration in dog and human bladders attained with the 40-mg dose (8.77 micrograms/g in dogs and 7.55 micrograms/g in humans) was about twice that achieved with the 20-mg dose (4.33 micrograms/g in dogs and 3.91 micrograms/g in humans). In dogs, the plasma concentration of MMC reached a steady state within 10 min; the mean maximal plasma concentration was 8.5 ng/ml. This plasma concentration is indistinguishable from the concentration derived from the 20-mg dose and indicates a minimal systemic exposure even at the higher dose. The average MMC concentration in tumor-bearing tissues was about 40% higher than the concentration in adjacent normal tissues (P = 0.01). In conclusion, the linear relationship between drug uptake in bladder tissues and drug concentration in urine supports the assumption used in the design of the ongoing Phase III clinical trial.

Bladder tissue pharmacokinetics of intravesical mitomycin C and suramin in dogs.

Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy.

Safety monitoring of the coliseum technique for heated intraoperative intraperitoneal chemotherapy with mitomycin C.

BACKGROUND: Treatment of carcinomatosis may involve the use of heated intraperitoneal chemotherapy; the cytotoxic solution is administered in the operating room with the abdomen open so that manual distribution results in uniform treatment. The potential risk of this procedure to the operating room personnel has not been previously investigated. METHODS: Mitomycin C was perfused through the peritoneal cavity, which was partially covered by a plastic sheet. Large volumes of air were suctioned from 5 and 35 cm above the abdominal skin edge. Urine from the surgeon and from the perfusionist were assayed. Sterile gloves worn in the operating room for manipulating the viscera during treatment were assayed for their permeability to mitomycin C. All samples were analyzed by high-performance liquid chromatography. RESULTS: Analysis of samples of operating room air and urine from 10 procedures showed no detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over 90 minutes. CONCLUSIONS: No detectable safety hazard to the surgeon or other operating room personnel was demonstrated.