The surgical aspects of the totally implantable hepatic artery infusion pump.

The design of a totally implantable hepatic artery infusion pump in 1969 made the use of hepatic artery infusion feasible and practical as a treatment for patients with hepatic neoplasms. The implantable pumps could function for long periods and reliably infuse a measured quantity of drug into the hepatic artery in a continuous fashion. This enabled oncologists to give much higher doses of chemotherapy directly into the blood supply of the tumors as well as to use a continuous infusion schedule.

Cancer surgery in the elderly.

The incidence of most cancers increases with age. Although the risk for surgery increases in elderly patients who have comorbidities, evaluations of risk can allow interventions that may decrease morbidity and mortality. Appropriate treatments should be offered to the elderly until studies demonstrate the elderly can safely be managed differently from younger patients. The elderly should not be denied adequate treatment simply because of age.

Superior survival of young women with malignant melanoma.

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) relating to patients with malignant melanoma are used to examine patterns of long-term survival by patient gender and age, stage of disease, disease morphology, and anatomic subsite. METHODS: Five calls for data have yielded more than 3,700,000 cases of cancer for the years 1985 through 1993, including 23,341 cases of malignant melanoma between 1985 and 1989, from hospital cancer registries across the US, representing slightly less than a quarter of all melanoma cases diagnosed in the US between 1985 and 1989. RESULTS: Three statements can be made from this data: (1) There is little difference in the frequency of malignant melanoma between men and women with respect to stage of disease or morphology. However, differences between the genders do appear with respect to the anatomic subsite of melanotic tumors. (2) Overall, young women (45 years of age and under) enjoy superior survival rates when compared with older women (55 years of age and older) and men of any age. (3) The survival advantage held by young women is particularly pronounced among patients diagnosed with advanced stage disease. CONCLUSIONS: These data suggest that factors present in younger women may be critical in the superior survival rates seen among premenopausal women and might be hormonal in nature.

The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy.

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.

Economic implications of hepatic arterial infusion chemotherapy in treatment of nonresectable colorectal liver metastases. Meta-Analysis Group in Cancer.

BACKGROUND: Approximately 20% of patients with colorectal cancer die of metastases confined to the liver. A meta-analysis recently performed by our group confirmed that in these patients hepatic arterial infusion of 5-fluoro-2'-deoxyuridine, compared with intravenous chemotherapy with fluoropyrimidines or supportive care (including symptom palliation when necessary), improved tumor response. PURPOSE: Because of the high cost of hepatic arterial infusion, we undertook a cost-effectiveness analysis that related the cost of such therapy to its medical efficacy. METHODS: The patient population was drawn from the seven randomized clinical trials included in the meta-analysis and included individual data on 654 patients. Of these seven trials, five compared hepatic arterial infusion and intravenous chemotherapy and two compared hepatic arterial infusion and a control group in which some patients could be left untreated. Patients assigned to receive hepatic arterial infusion made up the hepatic arterial infusion group; the other patients constituted the control group. The measures of efficacy were survival and tumor response. Health-care costs (in 1995 U.S. dollars) were computed over the duration of patient follow-up and were derived from actual costs in two centers, one at Henri Mondor Hospital (Paris, France) and the other at Stanford University Medical Center (Palo Alto, CA). The total cost of treatment included the initial procedure, chemotherapy cycles, and main complications. RESULTS: The mean gain in life expectancy in the hepatic arterial infusion group compared with the control group was 3.2 months (standard error = 1.0 month). For patients treated by hepatic arterial infusion in Paris, the hepatic arterial infusion pump, initial hospitalization, and the entire process (including follow-up and complications) cost, on average, $8400, $15172, and $29562, respectively; in Palo Alto, these costs were $4700, $13784, and $25 208, respectively. For patients in the control groups in Paris and Palo Alto, the total treatment costs were, on average, $9926 and $5928. The additional costs of hepatic arterial infusion over control treatment were $19636 in Paris and $19280 in Palo Alto. The cost-effectiveness (i.e., the additional cost divided by the additional benefit) with respect to survival of the patients in the hepatic arterial infusion group compared with the patients in the control group was $73635 per life-year in Paris and $72300 per life-year in Palo Alto. CONCLUSIONS AND IMPLICATIONS: The cost-effectiveness of localized chemotherapy for colorectal liver metastases is within the range of accepted treatments for serious medical conditions, although it might be considered borderline by policy-makers in some countries. Prospective clinical trials should be conducted to more definitively answer this question.

Breast cancer in the United States.

Breast cancer is a major health problem in the United States. The causative factors are not known so the prevention of breast cancer remains difficult. Treatment advances have taken place over the last 30 years to allow for less radical surgery and breast-conserving procedures. Now a woman who finds a small breast cancer does not have to face mastectomy as her only option. This will allow women to seek medical advice early if they find a breast mass. Although the breast-conserving procedures have been shown to be as effective as mastectomy their use is still low in the United States. The reasons for the preponderance of mastectomies are unclear. The future hopes for breast cancer are: (1) discovery of the causative factors so that a preventive method can be established; (2) more effective chemotherapy against established tumors; and (3) the discovery of markers of the aggressiveness of tumors so that the appropriate patients can be treated after surgery. With the increased public awareness of the magnitude of the health problem that breast cancer represents more funds are being earmarked for breast cancer research. In the near future we can hope medical scientists will be able to make the necessary strides to bring the disease under control.

Chemotherapy after hepatic resection of colorectal metastases.

Although it is excepted practice now that one to three hepatic metastases from colorectal primaries should be resected, it is not clear whether treatment with chemotherapy, either via the hepatic artery or a systemic vein, is necessary after resection. There is some evidence that intraarterial therapy may decrease the incidence of hepatic recurrences but we must wait for the completion of the intergroup trial on postoperative therapy before a definitive answer can be made for the use of intraarterial therapy after hepatic resection.

The effects on liver metastases of circadian patterned continuous hepatic artery infusion of FUDR.

Although continuous hepatic artery infusions (CHAI) of (FUDR) Floxuridine have been effective in reducing the size of colorectal hepatic metastases the toxicity of the infusions have been high with almost a quarter of the patients developing biliary sclerosis. Techniques to lower toxicity, yet continue the beneficial antitumor effects, are being investigated. One suggested strategy is to change the flow pattern of the continuous infusion from a constant rate to a day cycled pattern. In this infusion a continuous rate is given over a 24 hour period with 60% of the infusion delivered between 3 PM and 9 PM and the least amount of infusion delivered between 3 AM and 9 PM. Previous research has suggested that this day cycle pattern will lower the toxicity of the infusion. This experiment is a test of "day cycled" continuous hepatic artery infusions in rats bearing hepatic metastases from a colon adenocarcinoma. Previous research from our laboratory has shown a lowered toxicity when the constant infusion was replaced with the day cycled pattern. In the present study 10 rats with hepatic adenocarcinoma metastases were placed on constant CHAI of FUDR at 10mg/kg/day for 14 days. There was an 80% mortality from chemotherapy toxicity and a 90% objective response rate. Nine other rats were treated with "day cycled" CHAI of FUDR at 15mg/kg/d. There was no mortality in this group and the objective response rate was 90% as in the previous group. This study demonstrated that "day cycled" CHAI of FUDR was substantially less toxic and that the antitumor effect was identical to the constant infusion.

Splenectomy in patients with AIDS and AIDS-related complex.

OBJECTIVE: To study the effect of splenectomy in HIV-infected patients. DESIGN: A retrospective chart review of patients admitted to St Vincent's Hospital who had splenectomies and were HIV-positive. SETTING: All patients were treated at St Vincent's Hospital, New York City, New York, USA. PATIENTS: Only patients who were HIV-positive and who had had a splenectomy at St Vincent's Hospital were included. INTERVENTION: All patients had a splenectomy. MAIN OUTCOME MEASURES: The effect of the splenectomy in these HIV-positive patients was studied with respect to their operative morbidity and mortality, platelet counts, overall survival and the development of new opportunistic infections. RESULTS: All patients who did not have AIDS but did have thrombocytopenia responded to splenectomy in terms of their thrombocytopenia. None of them had an accelerated progression to AIDS. Most patients with AIDS and thrombocytopenia responded to splenectomy in terms of correcting their thrombocytopenia. CONCLUSIONS: Splenectomy as a treatment for thrombocytopenia is successful not only in HIV-positive patients without AIDS, but also in AIDS patients. However, in patients with disseminated Kaposi's sarcoma or Mycobacterium avium intracellulare, splenectomy may not be a factor for survival.

Jonasson, Braunwald, and Morani. Three firsts in American surgery.

The lives of three extraordinary surgeons who were among the earliest women in American surgery are chronicled herein. No written account can ever accurately reflect the hardships they suffered, or provide a true measure of their courage. Despite the support of colleagues, friends, and family, each crossed the new frontiers alone, in the face of great adversity. They survived, they endured, and ultimately they triumphed. What each has given back to her chosen profession has repaid, many times over, the training often reluctantly given. What each has conferred to those who come after is the conviction that it can be done and the strength to follow.

Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2.

Previous studies on continuous hepatic artery infusions of recombinant interleukin-2 (IL-2) have shown that in a nontumor-bearing animal a continuous infusion given in a circadian "day cycled" pattern was much less toxic and could be given with 10 times higher doses of IL-2 than if the constant pattern of infusion was used. In the present study, circadian-patterned continuous hepatic artery infusions of IL-2 were used in hepatoma-bearing rats. Doses of 10 mg/m2/day could be tolerated when IL-2 was given in a "day cycle" rhythm. Control animals were given 1 mg/m2/day of constant infusion IL-2, which was the highest hepatic artery infusion dose tolerated at a constant rate without mortality in nontumor-bearing animals. Animals treated with the constant infusions of IL-2 had a 37.5% mortality rate and a 25% objective response rate in measurable tumor size. Animals receiving the "day cycle" had no mortality and a 100% objective response rate. The conclusion was that "day cycled" circadian-patterned continuous hepatic artery infusions of IL-2 could be given with much lower toxicity and much improved tumor response rates than constant continuous infusions.

The effects on toxicity of circadian patterning of continuous hepatic artery infusion.

Long term continuous hepatic artery infusion of FUDR was carried out in 34 rats. In the animals who received a constant infusion schedule of 15 mg/kg/day all died of toxicity with a mean survival of 9.3 days. If the pattern of the continuous infusion was changed so that over 60% of the infusion was given during the hours of 3pm to 9pm than all of the animals survived the 14 day infusion. If the maximum dose of infusion was changed so that 60% of the infusion was given at night from 3am to 9am the infusion became more toxic and all the animals died in a mean of 5.5 days. Pathologic sectioning of all the livers reflected the above outcomes with the greatest amount of hepatic necrosis in the animals on the night cycles. This study underscores the recent advances in chronobiology demonstrating that for continuous hepatic arterial infusions the timing of delivery is crucial in determining the toxicity.