Plasma retinol level reduction by the synthetic retinoid fenretinide: a one year follow-up study of breast cancer patients.

Fenretinide (HPR) is a synthetic retinoid which has been shown to cause a reduction in the incidence of carcinogen-induced epithelial tumors in experimental animals, and it has been chosen to be tested as a chemopreventive agent in humans. A study on plasma concentrations of HPR, of its metabolite N-(4-methoxyphenyl)retinamide (MPR), and on its effects on endogenous retinol was performed in groups of 14 to 18 breast cancer patients who received p.o. daily doses of placebo or 100, 200, and 300 mg of HPR for 6 mo and subsequently 200 mg for an additional 6 mo. After the first 5 mo of treatment, there was a linear relationship between doses of HPR administered and HPR, MPR, and retinol levels. HPR and MPR levels increased with the increase in dose, whereas retinol levels decreased, and the reduction was statistically significant compared with the placebo group after all the doses tested. Plasma retinol binding proteins (RBP) decreased proportionally to retinol (r = 0.96). The effect of HPR on retinol and RBP occurred early, since retinol and RBP levels had already been decreased, compared with the initial levels, by 38% and 26%, respectively, 24 h after a 200-mg HPR dose. After 12 mo of treatment, in patients treated with 200 mg daily, the dose chosen for a chemopreventive trial, HPR and retinol levels were similar to those found at 5 mo, suggesting no drug accumulation and no further retinol reduction, whereas MPR levels were higher. Following interruption of treatment, as HPR decreased, retinol increased with a linear relationship between log levels (r = 0.78); after about 50 days, HPR was present in trace amounts, and retinol levels were in the range of those of the placebo group. These data show that HPR treatment lowers retinol and RBP plasma concentrations. This effect is related to HPR levels and is reversible on cessation of HPR administration.

Chest x-ray survey in breast cancer follow-up--a contrary view.

The authors report on 83 cases of intrathoracic 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 less than 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.

Psychologic aspects of patients participating in a phase I study with the synthetic retinoid 4-hydroxyphenyl retinamide.

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 mg/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.

Tolerability of the synthetic retinoid Fenretinide (HPR).

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.

Chest X-ray survey in the follow-up of breast cancer patients.

The authors report on 182 cases of intrathoracic metastases (ITM = lung, pleura or mediastinum) observed as first single recurrences in the course of the follow-up of patients treated for primary breast cancer. ITM were detected on standard two-views chest X-ray (CXR) at regular follow-up visits and in absence of subjective symptoms (102 A cases) or in the interval between two consecutive planned controls because of the onset of subjective symptoms (80 S cases). The average disease-free interval since primary treatment was significantly shorter in A with respect to S cases (40.3 vs. 28.5 months, P less than 0.001) as a consequence of the early detection achieved by CXR survey. On the contrary, prognosis was not influenced by ITM early diagnosis as the 10-year survival since primary treatment did not differ significantly between A or S cases (12% vs. 10%, P = 0.68). Results were confirmed on multivariate (Cox's) analysis, adjusting for potential confounders such as age or nodal status. Periodic CXR survey looks a very questionable policy as it does not seem to have any favourable impact on prognosis. Its routine use in breast cancer patients should thus be carefully reconsidered.

Fenretinide: prevençäo em pacientes tratados de carinoma de mama / Fenretinide: prevention in patients treated of breast carcinoma

A Fenretinide (HPR) é um retinóide sintético análogo à Vit. A que provou ser efetivo na prevençäo de tumores mamários em animais modelos. Este estudo, nesta fase I, foi proposto no Instituto Nacional dos Tumores de Miläo com o objetivo de avaliar a tolerância desta droga em humanos. Neste estudo, 101 pacientes com câncer de mama foram randomizadas em 4 grupos de acordo com a dose diária da droga: 100mg, 200mg, 300mg e placebo. Todas as pacientes foram operadas no mesmo Instituto e näo receberam nenhum tratamento adjuvante (endócrino ou quimioterápico). Exame clínico, testes sangüíneos de laboratório, avaliaçäo dermatológica e oftalmológica foram realizadas periodicamente. Uma paciente interrompeu o tratamento na 12ª semana, por terem sido demonstradas metástases ósseas e pulmonares. Cem pacientes completaram as 20 semanas de tratamento e näo apresentaram efeitos colaterais significativos. Em um caso foi necessário diminuir a dose por três dias com o objetivo de verificar a possível correlaçäo entre linfagite recorrente e o tratamento com HPR. A paciente tornou a utilizar a dose de 200mg/dia e os sintomas desapareceram independentemente. Uma cuidadosa avaliaçäo dos efeitos da droga sobre o ciclo menstrual demonstrou que as irregularidades observadas eram relacionadas muito mais com a idade da paciente do que com o uso da droga. Depressäo e labilidade emocional foram observadas em 18 casos. Todavia estes sintomas estavam presentes desde a semana zero e näo aumentaram de intensidade durante o tratamento. Durante as 20 semanas do estudo nenhum carcinoma na mama contralateral foi observado