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Bowel obstruction is a common and distressing outcome in patients with abdominal or pelvic cancer. Although surgery should be the primary treatment for malignant obstruction, it is now recognized that some patients with advanced disease or in generally poor condition are unfit for surgery and require alternative management to relieve distressing symptoms. A number of treatment options are now available for the patient with advanced and terminal cancer who develops intestinal obstruction. Medical measures such as analgesics, anti-secretory drugs and antiemetics may be used alone or in combination to relieve symptoms.

PURPOSE Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed. PATIENTS AND METHODS Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month. RESULTS 4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma. CONCLUSION 4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.

N-(4-hydroxyphenyl) retinamide (4-HPR) is a synthetic retinoid which reduces the incidence of experimental tumours in animals and has been chosen for its weak toxicity to be tested as a chemopreventive agent in humans. The mechanism of antineoplastic action is still unknown but a possible immunoenhancing effect may be postulated. We investigated the NK activity of PBMC from a group of women treated with 4-HPR as a part of a large scale randomised phase III trial on chemoprevention of contralateral disease in mastectomised women. After 180 days of treatment the NK activity was augmented 1.73 times as compared to that of patients given a placebo. The NK activity of PBMC from 4-HPR treated women is maximised, being higher than the basal and even the rIL-2 or alfa-rIFN stimulated activity of controls. For this reason in the majority of cases it cannot be further augmented by incubation with either rIL-2 or alfa-rIFN in vitro. The increased NK activity of 4-HPR treated women is not due to an enhanced production of endogenous IL-2, because PBMC cultures from patients treated with 4-HPR or placebo, incubated in vitro with a panel of different stimulators (recall antigens, PHA, allogeneic and xenogeneic cells) produce similar amounts of IL-2. The functional activity, but not the number of NK cells is increased in 4-HPR treated women. The mechanism by which 4-HPR stimulates NK activity is not a function of direct action on NK cells. Indeed incubation of PBMC from blood donors with 4-HPR or its major metabolite N-(4-methoxyphenyl) retinamide (4-MPR) does not modify their natural cytotoxicity.

The risk of developing breast cancer was investigated in 339 patients in whom histologically confirmed intraductal papilloma had been surgically removed. Follow-up ranged from 2 to 14 years, (average, 6.62 years). Ten breast cancers were observed, whereas 3 were expected on the basis of age-specific incidence rates drawn from local cancer registries (relative risk = 3.33, 95% confidence interval = 1.60-6.13). No significant difference in the relative risk was observed as far as papilloma type (single or multiple) was concerned. All breast cancers observed occurred in the same breast as the papilloma. Women in whom a benign intraductal papilloma has been excised should be carefully followed since they at are higher risk for ipsilateral breast cancer.

A group of 53 patients initially participating in a phase I trial with the synthetic retinoid fenretinide was assessed for the long-term tolerability of this compound. The patients were evaluated after 42 months of drug intake at a dose of 200 mg/day, including a 3-day drug interruption at the end of each month, by the following examinations: a dermatological visit; an ophthalmological evaluation including an ophthalmological questionnaire and an electroretinogram (ERG); a study on blood chemistry and plasma retinol levels; a study on bone densities and on skeletal X-rays; and finally a psychological evaluation including various tests for anxiety, depression and overall mood. The results show that prolonged administration of fenretinide is well tolerated. No acute nor severe toxicity was observed and thus this compound can be considered a good candidate for chemoprevention trials in a variety of patient populations.

Five hundred and thirty-nine patients with carcinoma of the breast treated with total axillary dissection and with positive axillary nodes were evaluated. The total number of lymph nodes removed was 11,082, with an average of 20.5 nodes per patient. The average number of lymph nodes at the first level was 13.8, at the second level 4.5, at the third level 2.2. The average number of nodes was 20.7 in cases treated with Halsted mastectomy, 20.9 with total mastectomy and axillary dissection, 20.3 with quadrantectomy and axillary dissection. Of 3259 metastatic nodes, 64 were site of micrometastases; 797 were partially involved, 441 were totally involved and 1957 were site of metastases with extracapsular invasion. In 314 (58.2%) the first level only was involved, in 117 cases (21.7%) metastases were present at the first and second level, whereas in 88 cases (16.3%) all the three levels were sites of metastases. Only 20 cases showed skipping distribution. In 1.5% of the cases the first level was skipped by metastases, in 0.4% the first and second levels were both skipped. The predicting value of the first level is considerable: when the nodes of the first level are clear the chances that metastatic nodes are present at the second and third levels are negligible. When the nodes at the first level are positive, the chances that metastases are also present at the higher levels are of the order of 40.0%. Cancer 59:682-687, 1987.

One hundred and one patients participating in a phase I study with the synthetic retinoid 4-HPR (4-hydroxyphenyl retinamide) were evaluated. The study was set up by Veronesi et al. during 1986 at the National Cancer Institute of Milan. The patients were randomized into 4 groups. of therapy: 25 in the placebo group, 25 in the group receiving a daily dose of 100 mg of HPR, 26 in the group receiving 200 nig/day of HPR, and 25 in the group receiving 300 mg/day of HPR. All patients were previously treated at our Institute for breast cancer. None had received adjuvant therapy, chemotherapy or hormone therapy. After 4–5 months from the beginning of treatment, all patients received a series of tests to evaluate anxiety, depression and sexual life. Moreover, during one the follow-up checkups after 4–5 months, the patients filled-out a self-scoring mood questionnaire. The results did not show any particular differences between the groups, although we found that the administered drug and experimental setting do not interfere with the psychologic state of the participating patients.

Fenretinide®, N-(4-hydroxyphenyl)retinamide (HPR), is a synthetic retinoid which has been proven effective in inducing cell differentiation and in inhibiting carcinogen induced mammary tumors in rodents. Because of its efficacy and low toxicity in animals, HPR has been proposed for chemopreventive evaluation in humans. Thus, a randomized trial has been conducted to select a dose which can be administered over a lengthy period of time and with acceptable toxicity. The retinoid was administered orally to patients already operated on for breast cancer in daily doses of 100, 200 and 300 mg for 6 months and subsequently at 200 mg for another 6 months. No acute toxicity was found. Dermatological toxicity was minimal and no liver function abnormalities were observed. Nausea and headaches were infrequent and always mild. Menstrual irregularities were recorded with similar frequency in the treatment and placebo groups and appeared to be more age related than drug dependent. After 6 months of treatment one of 25 patients taking 300 mg HPR daily experienced impaired night vision, confirmed by the electroretinogram, and resolved by interruption of treatment. Because the 300 mg daily dose is possibly associated with impaired dark adaptation, the recommended dose for chemoprevention trials of HPR is 200 mg per day.

The authors report on 83 cases of introthoracic metastases (ITM) observed as isolated first recurrences in a ten-year experience of periodic chest x-ray (CXR) survey of primary breast cancer. In 44 of 83 cases ITM were detected on CXR in absence of subjective symptoms or clinical signs (A) whereas 39 ITM cases were detected as subjectively (S) symptomatic in the interval between two planned CXR controls. Diagnosis was anticipated by CXR survey as the disease-free interval was significantly shorter (30 vs. 43 months, p < 0.04) for A respect to S cases. Nevertheless such a diagnostic anticipation had no prognostic impact as the ten year survival from primary treatment did not differ (0.12 vs. 0.16, p = 0.6) between A and S cases. Multivariate analysis confirmed that no impact on survival from primary treatment is expected whether ITM are detected in an earlier (asymptomatic, preclinical) or in a more advanced (subjectively symptomatic) phase. CXR survey after primary treatment of breast cancer seems thus a very questionable policy.

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial originally designed and conducted by the investigators of the Istituto Nazionale Tumori of Milan. The study is sponsored by the National Cancer Institute of Bethesda and by the Italian National Research Council. The trial was designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in a population of patients previously operated on for breast cancer. Between 1987 and 1993, the Istituto Nazionale Tumori of Milan and 9 other collaborating Centers enrolled 2,972 women between the ages of 30 and 70 years who had been previously operated on for T1-T2 N- M0 breast cancer. This paper describes the rationale, design, methodology, organization, data management, statistics and accrual of the participating population.