Search

Colorectal cancer is the second leading cause of cancer mortality in the United States, causing approximately 50,000 deaths per year. The overall prognosis and results of treatment have not changed impressively over the last three decades. Half of all the patients who undergo curative surgery finally succumb to locoregional or metastatic recurrence of their disease. Recent clinical research has been aimed at adjuvant therapeutic measures to improve survival after curative surgical resection. For rectal cancer, combined postoperative chemotherapy and radiation therapy have been shown to reduce the overall relapse rate and improve disease-free survival. Further studies of adjuvant treatment for rectal cancer are needed to evaluate the optimal radiation schedule and limit the side-effects of the treatment. Adjuvant treatment of colon cancer must still be regarded as unsettled. Since liver metastases are the most common unfavorable outcome of colon cancer, ongoing trials using liver-directed treatment (perfusion, irradiation) should be followed with interest. The lack of proven efficacy and the side-effects of these treatments strongly favor the inclusion of an observation-only control group in trials for adjuvant treatment of colon cancer. Unfortunately, there is as yet no proven significant benefit from immunotherapy as an adjuvant therapy for colorectal cancer, but further basic and clinical studies will be of great interest in this field. [ABSTRACT FROM AUTHOR]

Bisantrene (NSC-337766) was administered to five patients with cancer of the liver (one case of hepatocellular carcinoma, two of metastatic carcinoma of unknown primary, two of metastatic colorectal carcinoma). Under fluoroscopic guidance, percutaneous hepatic venous catheters were placed in five patients and percutaneous hepatic arterial catheters in four. A fifth patient's hepatic arterial catheter was implanted at laparotomy. Hepatic plasma flow was estimated by the Fick principle using peripheral vein indocyanine green infusion. On the first day of treatment, patients received a 2- or 4 h hepatic arterial infusion of bisantrene (130 mg/m2); peripheral venous, hepatic arterial, and hepatic venous timed blood samples were drawn during and for 18 h after drug infusion. On the second day of treatment, 2- or 4 h peripheral vein infusion of bisantrene (130 mg/m2) was followed by the same blood sampling schedule. Patients were followed weekly for toxicity. Four patients received only one course of treatment, while a fifth received two courses. All patients experienced leukopenia (median nadir 2400/mm3; range 1400-2700/mm3). Two patients developed fever after drug infusion. No antitumor responses were observed. Plasma bisantrene concentrations were measured by HPLC. Pharmacokinetic analyses are reported for four patients. The hepatic extraction ratio ranged from 15% to 49%, hepatic plasma clearances were 0.029-0.353 1/min/m2; peripheral vein areas under the concentration-time curve during hepatic arterial infusion ranged from 35% to 50% of peripheral vein areas under the curve during peripheral vein infusion. We conclude that hepatic arterial bisantrene infusion offers only modest pharmacokinetic advantage to the target organ or to the systemic circulation over peripheral vein infusion. [ABSTRACT FROM AUTHOR]

Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease., Methods: Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months., Results: At the end of treatment. 47% (7 of 15) of ISIS 2302-treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302-treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302-treated patients. These findings were corroborated by significant increases in beta7 and alpha d bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period., Conclusions: ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.

Healthy male volunteers received single or multiple intravenous infusions of an intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in a rising-dose (0.06-2.00 mg/kg infused over 2 hr), double-blind, placebo-controlled trial. Brief, dose-related increases in activated partial thromboplastin time were seen at the time of peak plasma concentration (C(max)). Clinically insignificant increases in C3a were seen after higher, repeated doses, but C5a, blood pressure and pulse were unaffected. No adverse events or other laboratory abnormalities were related to treatment with the drug. ISIS 2302 C(max) was linearly related to dose and occurred at the end of infusion. Plasma half-life for intact drug (53-54 min) and total oligonucleotide (67-74 min) were similar at the two doses (0.5 and 2.0 mg/kg) at which extensive pharmacokinetic data were collected. Nonlinear changes in area under the plasma concentration/time curve and steady-state volume of distribution with increasing dose suggested a saturable component to disposition. Metabolites co-migrating with n-1, n-2 and n-3 chain-shortened versions of ISIS 2302 appeared very rapidly in plasma, and disposition and metabolism appeared unaltered by repeated dosing. ISIS 2302 was well tolerated and behaved reproducibly with respect to plasma pharmacokinetics and expected side effects.

The antitumor activity of Carbetimer was tested against 171 patient's tumors in a human tumor cloning system. Sixty-seven tumor specimens had adequate growth to be considered evaluable. In 21 specimens survival of tumor colony forming units was less than or equal to 50% that in control plates. Antitumor effect was most impressive in carcinomas of the breast, ovary, and lung. This information will be useful in planning disease oriented Phase II trials.

We have utilized a human tumor cloning system to determine the in vitro antitumor effects of elliptinium, a new DNA intercalating agent. The purpose was to determine which human tumors should be studied in phase II clinical trials with this agent. Eighty-eight out of 282 tumors plated in culture were evaluable for drug-sensitivity assays. The overall in vitro response rate (defined as a less than or equal to 50% survival of tumor colony-forming units compared to control) was 28% at 0.4 micrograms/ml (1/10 of peak plasma level). In vitro activity was noted for elliptinium against breast cancer, renal cell carcinoma, small-cell lung cancer and non small-cell lung cancer. Elliptinium had a higher in vitro activity than adriamycin against this same group of tumors. Six of 25 (24%) adriamycin-resistant tumors were sensitive to elliptimium. Our in vitro response rate in breast cancer correlates with the response rate in phase II clinical trials with this drug. Further phase II clinical trials with elliptinium in patients with renal cell carcinoma, non small-cell lung cancer and small-cell lung cancer are indicated.

7-con-O-Methylnogaril (menogaril, NSC-269148) is a new anthracycline antibiotic that has been evaluated in a Phase I clinical trial. The drug was administered in a single i.v. infusion over a period of 60 min given every 3 weeks. Twenty-four patients received 64 courses of the drug in a dose range of 16 to 256 mg/m2. Granulocytopenia was dose limiting and prolonged, requiring treatment delay in 5 of 9 patients treated at doses greater than or equal to 192 mg/m2. Concentration dependent phlebitis occurred in 12 patients, and was of minimal severity when the menogaril concentration was less than 1 mg/ml. Hair loss was experienced by 8 patients but was generally mild with only one patient developing total alopecia. Possible acute cardiac toxicity was noted in one patient who had a transient episode of atrial fibrillation following his fifth course of menogaril. Phase II studies of 7-con-O-methylnogaril are planned at a starting dose of 160 mg/m2 for patients with prior chemotherapy or radiotherapy, and 200 mg/m2 for those without prior therapy given at 28-day intervals.

Since pancreatic cancer is still increasing and has a poor prognosis, there is great interest in improving treatment results by combined modality approaches. This paper considers the most appropriate studies to analyze the status of treatment and future implications for surgeons. With new radiation sources and more sophisticated treatment plans, intra- and post-operative radiotherapy now has an established role in local tumor control. Combination chemotherapy has yielded response rates of 40-45% and improved chemotherapy will play a role in the treatment and perhaps in the prevention of disseminated disease. Although it seems likely that chemotherapy combined with newer radiotherapeutic technique could improve treatment results in advanced pancreatic cancer, treatment-related and limiting toxicity still must be defined. There are suggestions that more surgeons become involved in the combined modality approach, as both radiotherapy and chemotherapy may be more valuable in primary management. The unsatisfactory results of surgical treatment imply the need for adjuvant treatment, which must be tested in randomized multicenter trials. Future efforts will require an interdisciplinary approach to this disease.

A human tumor cloning system was utilized to screen for the antitumor activity of recombinant interferon alfa-2b (Intron A) alone and in combination with standard antineoplastic agents. These in vitro studies confirmed synergistic effects of alfa-2b plus doxorubicin against primary human tumors. Based on those in vitro findings, a phase I study has been conducted by Sarosy and colleagues that demonstrated that recombinant interferon alpha-2b and doxorubicin could be given together. Myelosuppression was the dose-limiting toxicity. Because responses were noted in the phase I trials with the combination, phase II trials of the combination are warranted. Additional phase I studies that should be pursued include recombinant interferon alpha-2b plus 5-fluorouracil, interferon plus cisplatinum, and interferon plus DTIC.

Carbetimer (carbethimer, N-137, NED-137, carboxyimamidate) is a low molecular weight polyelectrolyte with antitumor activity in a variety of tumor models. This phase I trial evaluated a single dose of carbetimer infused over 1-2 h every 28 days. Forty-three patients received 71 courses of the drug at doses ranging from 180 to 8500 mg/m2. The dose-limiting toxicity was hypercalcemia (serum calcium greater than 12.5 mg/dl) noted in two of three patients at a dose of 8500 mg/m2. Serum calcium levels between 10.5 and 12.5 mg/dl were noted in an additional three patients treated at doses greater than or equal to 1600 mg/m2. Calcium balance studies in three patients treated at 6500 mg/m2 revealed an increase in urinary cyclic AMP and phosphate excretion after treatment accompanied by a mild elevation of serum parathyroid hormone. Immunological studies in these patients revealed a statistically significant increase in the percentage of peripheral T-helper cells. An increase in the T-helper/suppressor cell ratio was observed in two of the three patients studied. Interleukin 2 production by phytohemagglutinin-stimulated peripheral mononuclear cells was increased in two of three patients. One patient with a renal cell carcinoma showed a mixed response. The recommended dose for phase II trials as assessed from this study is 6500 mg/m2 as a single dose every 28 days.

Cytotoxic chemotherapy and interferon have shown synergistic antitumor activity in vitro. The purpose of this study was to determine the maximally tolerated dose of doxorubicin given every 3 weeks, in patients receiving recombinant alpha 2-interferon [10 X 10(6) IU/m2 s.c. three times per week (Monday, Wednesday, and Friday)] during the first 2 weeks of each cycle of doxorubicin. Fourteen patients received a total of 41 cycles. Hematological toxicity was dose limiting with granulocytopenia (total granulocyte count, less than 1000) occurring in 50% of patients treated with doxorubicin at 40 mg/m2 and in 25% of patients treated with doxorubicin at 30 mg/m2. Nonhematological toxicities included a flu-like syndrome, alopecia, nausea, vomiting, diarrhea, and transient mild increases in liver function tests. A partial response was seen in one patient with metastatic squamous cell carcinoma of the skin and in another patient with metastatic adenocarcinoma of the pancreas. Concomitant administration of recombinant alpha 2-interferon given on this schedule limits the amount of doxorubicin that can be administered. However, the responses noted in this study are encouraging enough to warrant additional studies of doxorubicin plus recombinant alpha 2-interferon.

Since 1958 there has been intense efforts in adjuvant systemic therapy for colorectal cancer. Peri-operative chemotherapy with HN2, TSPA + FUDR produced no clear-cut prolongation of disease-free survival. Short-term (two courses) and long-term (18 months) therapy with 5-FU by the Veterans Administration surgical Adjuvant Group is reported to give marginal increases (7--9%) in survival at 5 years. These findings are confirmed by the COG study of prolonged 5-FU which shows prolongation of disease-free survival of borderline statistical significance for Dukes' C colon (P = 0.051) + rectum (P = 0.016). Short-term benefit to 18 months was conferred by prolonged 5-FU in the VASAG + COG studies, for patients who have had a palliative resection. Combination chemotherapy might be more active, but no results are available from the controlled trials utilizing 5-FU + MeCCNU or immunotherapy. Preoperative irradiation in the VASAG studies resulted in downstaging in terms of operative findings of lymph node involvement and was of survival benefit in those patients have an AP resection for cure or palliation of rectal cancer (P less than 0.02). More intensive preoperative radiation programs are ongoing, as well as postoperative radiation with and without chemotherapy. Further progress awaits the discovery of truly active chemotherapy programs, as well as better techniques of radiation enhancement.