Arnold Mittelman

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.

Phase I clinical trial of recombinant human tumor necrosis factor

SummaryA phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48x104 units/m2. Drug was given as 1-h i. v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath, were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearnance and a short plasma half-life, generally less than 0.5 h.

Polyamine biosynthetic activity in normal and neoplastic human colorectal tissues

Polyamine biosynthetic activity was assessed in various colorectal tissue samples consisting of noninvolved mucosa, benign adenomatous polyps and adenocarcinomas taken at surgery from a total of 40 patients. Ornithine decarboxylase (ODC) displayed a gradient of enzyme activity (i.e., adenocarcinoma > polyps > mucosa) which seemed to correlate positively with the neoplastic status of the tissue. In 10 of the patients, samples were obtained for all three tissue types. Five of these exhibited a clear repetition of the trends in enzyme activity seen with the mixed patient tissue sampling whereas the remainder differed by having the highest ODC activity in the polyps. In nine of the ten cases, ODC activity was substantially lower in the mucosa than in either of the neoplastic lesions. Trends in enzyme activity were the same for tissues obtained from either the colon or rectum. The ODC activity in adenocarcinomas could not be correlated with histologic differentiation, stage or site of the disease, however, in samples from female patients (all postmenopausal) the activity was elevated over normal mucosa to a greater extent (ten‐fold) than in male patients (seven‐fold). S‐adenosylmethionine decarboxylase activity was assessed in 27 of the 40 patients and found to follow the same distribution as ODC; however, the mean value differences ± SEM between tissues were less distinct. In general, tissue polyamine pool analysis of these same specimens reflected the levels of ornithine and S‐adenosylmethionine decarboxylase activities. Overall, the data reveal an increase in polyamine biosynthetic activity in colorectal neoplasms, relative to surrounding mucosa, which may correlate with (1) progression of the neoplastic process, (2) the proportion of proliferating cells, (3) the rate of cell proliferation, or (4) a combination of two or all of these possibilities.

Malignant epithelial tumors of the anal canal

A simplified staging for malignant epithelial tumors of the anal canal is presented. The pattern of recurrence in males is pelvic and perineum, in females pelvis and posterior vaginal wall. Concomitant posterior vaginectomy is advocated. The disease is more common in females than males (4:1). There is little difference between histologic types, i.e. cloacagenic or squamous cell type. Recurrence and survival depend upon depth of invasion and extent of spread rather than histologic cell type. The tumors respond to well‐designed surgery, radiotherapy and probably chemotherapy.

Renal toxicity in man treated with mitomycin C

Thirty‐two patients with metastatic carcinomas were treated with mitomycin C. Three of them developed renal toxicity within 6 to 7 months of therapy. The toxic effect was mainly on the glomerular tuft and especially on the nuclei. Nephrotoxicity of mitomycin C has been noticed in rhesus monkeys, but has never been reported in man. Patients who are being treated with mitomycin C should be observed for a rising blood urea nitrogen, serum creatinine, and albuminuria.

Survival and response to chemotherapy for advanced colorectal adenocarcinoma. An eastern cooperative oncology group report

A series of 1,314 cases of advanced measurable colon or rectal cancer were evaluated for objective tumor response and survival. All patients received chemotherapy according to protocols conducted by the Eastern Cooperative Oncology Group during the period between 1974 and 1977. For those patients who had not received chemotherapy prior to study entry, no therapy program under evaluations was significantly more active than the oral or intravenous 5‐fluorouracil treatment programs with respect to survival or objective tumor response. The survival and response rates therapy programs under study, including methyl‐CCNU, appeared to be comparable. Initial performance status (P < 0.001), weight loss in the six months prior to study entry (P < 0.001), and prior chemotherapy status were shown to be most prognostic for survival, and thus merit inclusion as stratification factors in any comparative trial involving this population. These factors were shown to have a cumulatively greater influence upon survival than the treatment program. Treatment differences were most accentuated within the favorable subgroups of the leading prognostic factors. The location of the primary tumor had a significant effect upon the eventual sites of metastatic disease involvement at the time of study entry (P < 0.001). The consequences of this analysis suggest that investigators need to address characteristics of the population under study. It is also noted that patients with chemotherapy prior to study entry are best suited for survival studies, while patients with no chemotherapy prior to study entry are well suited for both objective tumor response and survival studies.

Surgical resection of pulmonary metastases from colorectal adenocarcinoma

From 1962 to 1982, 27 patients with pulmonary metastases as the only site of recurrent colorectal carcinoma underwent pulmonary resection at Roswell Park Memorial Institute. Only five of these patients had symptomatic pulmonary lesions. No postoperative mortality occurred. The median survival after pulmonary resection was 27 months. Five patients are alive presently without recurrent colorectal cancer and two patients are alive with recurrent pulmonary metastases. Patients with solitary lesions had a better survival than patients with multiple lesions. The major sites of recurrence following thoracotomy were the lungs and liver.

The use of colonoscopy in the study of synchronous colorectal neoplasms.

Over a 5‐year period, 185 patients with a primary colorectal carcinoma were studied by colonoscopy for synchronous neoplasms. Twenty‐eight patients had incomplete examinations due to obstructing tumors, and 157 had total colonoscopy. Sixty patients (35.9%) had synchronous neoplasms, of which 43 (25.7%) were adenomatous polyps, 5 (3%) were villous polyps, and 12 (7.2%) were carcinomas. The planned surgical procedure was altered on 7 of 12 synchronous cancers (58.3%), 10 of 38 adenomatous polyps, and 17 of 157 (10.8%) patients who underwent total colonoscopy. Preoperative colonoscopy is deemed essential for the optimal management of the patient with colorectal carcinoma.

Photodynamic therapy in patients with colorectal cancer

A pilot study was conducted, in which photodynamic therapy (PDT), a technique in which malignant cells are destroyed by light after being previously photosensitized by a chemical compound, was tried in a group of 14 patients with recurrent or residual colorectal cancer in the pelvis. Three of the six patients with unresectable pelvic recurrences experienced a significant relief of pain after PDT. In two of the five patients who had an incomplete resection of their pelvic recurrences, there was also a substantial relief of pelvic pain after surgery and PDT. In one of these patients subsequent biopsies proved the disappearance of the residual pelvic microscopic disease after several sessions of PDT. Three patients had a recurrence from a squamous cell carcinoma primary of the anal canal. All recurrences were amenable to surgical resection. In one of the patients, PDT was used in an attempt to sterilize an area of residual tumor that was located over the left ischial tuberosity. The patient experienced good relief of pain, but died of her disease 7 months after PDT. In the other two patients, PDT was used as an „adjunct”︁ after resection of their recurrences. One of these patients was free of disease and died of an unrelated cause 12 months after PDT. The other is alive and well. This study demonstrated that PDT can be safe and tolerable in patients with pelvic malignancies. PDT is capable of tumor destruction, can be used repeatedly in areas previously exposed to ionizing radiation, and may have a role in the prevention and management of pelvic‐perineal recurrences from colorectal cancer.

Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma

Plasma pharmacokinetics of high-dose (500 mg/m2) leucovorin calcium (dl-5-formyltetrahydrofolic acid [dl-CF]) and fluorouracil (FUra) have been evaluated in patients with advanced colorectal cancer treated with the combination of FUra and dl-CF by two different intravenous (IV) schedules: (A) In patients with no prior chemotherapy, dl-CF was administered by a two-hour IV infusion and FUra by rapid IV injection one hour after the start of the dl-CF infusion and (B) in previously treated patients, dl-CF and FUra were administered by five-day continuous IV infusion (CI). Following the two-hour infusion of dl-CF, mean peak plasma concentration and elimination half-life of I-5-formyltetrahydrofolic acid (I-CF) were 24 +/- 6 mumol/L and 0.8 +/- 0.1 hour, respectively. CI of dl-CF over five days yielded a mean steady-state plasma level of I-CF of only 1.2 +/- 0.5 mumol/L. Peak and steady-state plasma concentrations of the metabolite 5-methyl tetrahydrofolic acid were comparable in the two schedules (17 +/- 8 mumol/L for the two-hour infusion and 12 +/- 5 mumol/L for the CI). Areas under the concentration v time curve (AUC) of total reduced folates were significantly greater under conditions of CI: 89.0 v 16.7 mmol/L/min for the two-hour infusion. In tumor tissue, 5,10-methylenetetrahydrofolate increased eight-fold two to four hours following the two-hour infusion and two-fold during the CI of dl-CF and FUra. Inhibition of thymidylate synthase (dTMP-S) by the two-hour and CI infusion schedules were 66% v 39%, respectively. The observed differences in the intracellular dTMP-S folate cofactor pools and the degree of inhibition of dTMP-S achieved in patients treated by two different schedules may be due to differences in the biochemical properties and/or to differences in the modulation of FUra metabolism by folate of tumor tissues obtained from newly diagnosed and previously treated patients.