Biomedical subjects
Publications and source records attributed to M Espie.
Cancer chemoprevention needs carefully controlled clinical trials, definition of study populations and well selected chemopreventive agents. Randomized clinical trials are on going. We tried to summarize studies in the head and neck, lung, stomach, oesophagus, skin, bladder and cervix regions.
Tamoxifen and retinoids are actually studied for breast cancer chemoprevention. The role of fat intake, vitamins, selenium, alcohol consumption and progestins are reviewed in view of prevention trials.
There is a high risk of neoplasm in dysgenetic gonads. Classically, in Turner syndrome, only patients with 45, X/46, XY mosaicism karyotype or with a fragment of Y chromosome (45, X+mar) are at risk of developing gonadal tumor. A case of a dysgerminoma arisen on the dysgenetic gonad of a 45, X Turner patient in the absence of Y chromosome material at cytogenetic and molecular biology analysis is reported. Five cases of gonadal tumor with a pure 45, X chromosome constitution have been previously reported in the literature. In these cases only cytogenetic analysis was performed. This is the first case of an ovarian tumor in a 45, X Turner syndrome in which the presence of Y material can be ruled out by an extensive molecular analysis of the blood and the tumor.
Medulloblastoma is a rare tumor in adult. High doses of megavoltage irradiation of the posterior fossa have been resulted in a better survival (48 to 78% at 5 years) of the patient. It is sensitive to a wide variety of chemotherapy drugs, but adjuvant chemotherapy has not been proved effective in adults although data are limited. We report the case of a cerebellar medulloblastoma with bony and medullar metastases. High-dose chemotherapy with peripheral stem-cell transplantation was performed while the patient was in remission following conventional chemotherapy. Complete remission lasted for 8 months. This therapeutic approach of metastatic medulloblastoma might be of value as this tumor is chemosensitive and not cured by conventional treatment. Internal radiotherapy by Samarium-153 was also carried out and proved to be an effective palliative treatment of pain.
Hormonal therapy of breast cancer is the oldest treatment in advanced disease. Durable remissions can be obtained with a wide variety of hormonal manipulations. Oophorectomy was first used to reduce endogenous hormonal levels. Surgical procedures have been supplanted by drugs that reduce hormone secretion or block steroid hormone activity. Tamoxifen is the agent most widely used because of few side effects. Agonists can also be effective. Estrogens, androgens, and progestins have the same level of activity as surgical ablation or drug antagonists (20-40% overall response rate). More than 2,000 patients with advanced breast cancer worldwide have been treated with megestrol acetate in clinical trials. Reports of the trials show a response rate of 27%. In randomized trials, efficacy of megestrol acetate is comparable with tamoxifen and with other hormonal treatments. At the standard dose of 160 mg/day, the major side effect is weight gain. Studies are ongoing to evaluate if high doses of megestrol acetate may increase the response rate with acceptable toxicity.
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Taxoids (paclitaxel and docetaxel) are a new class of cytotoxic agents. Their mechanism of action (enhanced polymerization of tubulin and inhibition of its depolymerization) acts thereby as mitotic spindle inhibitors. Significant experimental antitumor activity, although more marked with docetaxel, has been observed with both agents. Their main side-effects are reversible non cumulative neutropenia and alopecia; significant hypersensitivity reactions using cortico-steroids antiHT1/2 premedication are seen in < 5% of patients receiving paclitaxel as a pulsed (3 h) infusion; neurotoxicity appears dose-related; docetaxel can induce a peculiar skin toxicity often associated with edema. Paclitaxel at the recommended dose of 175 mg/m2 achieves responses in 20-30% of patients with relapsed ovarian carcinoma; its activity in advanced breast cancer although significant is clearly dose-related with an optimal dose still debatable; responses are observed in approximately 30% of patients with non small cell lung cancer (NSCLC). Docetaxel (100 mg/2) is active in first line treatment of advanced breast cancer (50-72% RR) as well as 2nd line treatment (> 40% RR); an activity in the range of that observed with paclitaxel is reported in NSCLC.
Oxaliplatin, or trans-1-diaminocyclohexane-platinum, was tested in a phase I study. A total of 44 patients received 116 courses with dose escalation from 45 to 200 mg/m2. Neither renal nor hematologic toxicities were observed at doses up to 200 mg/m2. Gastrointestinal toxicity was practically constant and often of grade 3-4 on the WHO scale (53% of patients). The dose-limiting toxicity was a peculiar sensory neuropathy; the first neurologic phenomena appeared at a dose of 135 mg/m2 and continued thereafter, occurring after 75% of the courses with mild to moderate intensity (WHO grade 1-2 after 67% of the courses). Neurotoxicity was cumulative and six patients developed grade 3 disabling neuropathy after a cumulative dose of 500 mg/m2, with walking and handwriting difficulties being slowly regressive in three cases. A peculiar symptom was the influence of temperature, with exacerbation of parethesias when patients touched cold surfaces. Nerve-conduction studies carried out in six cases showed a predominantly sensory neuropathy with axonal degeneration. No other toxicities were observed, although audiograms were not systematically done. We observed four partial responses that lasted 6-13 months in patients with oesophageal (2 cases), lung (1), and urothelial cancer (1); two of these patients had been pretreated with cisplatin. Since neurologic side effects occur very frequently and may produce a long-lasting sensory neuropathy, for phase II studies we recommend a starting dose of 135 mg/m2, with a careful neurologic survey.
Chemotherapy-induced emesis is the most severe side effect in term of patient's perception. Current anti-emetic regimen as high dose metoclopramide can achieve a complete response in less than 60% of patients. The HT3 receptors appear to be the principal mediator of the emetic effect and their blockade have a clear activity in the prevention of acute drug-induced emesis, superior to reference regimens.
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High dose chemotherapy with autologous bone marrow transplantation has been proposed in metastatic and inflammatory breast cancer. Data in the literature reported an improvement of the quality and of the rate of response. However, the impact on survival remains to be demonstrated. Since 1985, a pilot study in inflammatory and directly metastatic breast cancer has been started in order to determine the impact of high dose chemo-radiotherapy. Patients were treated with an induction regimen consisting of cyclophosphamide 1,200 mg/m2 and 4'epi-adriamycin 75 mg/m2 every 15 days x 4. Mastectomy was performed associated for patients younger than 50 years with bone marrow collection and cryoconservation. In this group, late intensification with cyclophosphamide 2.2 g/m2 day 1 and 2, TBI and autologous bone marrow transplantation was performed. Fourteen patients have been treated: 9 inflammatory breast cancers T4 b N1 M0, 5 metastatic cancers at presentation including 3 with inflammatory breast cancer T4 b N1 M1 and 2 metastatic T2 N1 M1. Relapses had occurred in 7 patients, of them 4 were metastatic. Five patients died from their disease, and one from CMV interstitial pneumonitis. Six patients are alive free of disease but only one was metastatic. On this limited number of patients, survival of metastatic breast cancers does not seem to benefit from this regimen.
Vinorelbine (Navelbine) is a new semisynthetic vinca alkaloid which chemically differs from vinblastine by substitutions on the catharantine moiety of the molecule. It has shown promising experimental antitumor activity against experimental murine tumors as well as continuous cell lines of human neoplastic origin and human tumor xenografts in nude mice. Acute subacute and chronic toxicity extensively studied in rodents, dogs and primate has shown that hematotoxicity was almost the sole side-effect; neurotoxicity appears very limited. Almost exclusive affinity of NVB for mitotic tubulin and tubulin associated protein accounts for this pattern of toxicity. Phase I and II studies have been conducted in humans. Dose limiting side-effect appears to be neutropenia: the drug is slightly emetogenic, induces little alopecia, almost no neurotoxicity, and no other toxicity. Although preliminary, results of phase II studies already suggest significant activity of NVB in non small lung cancer (33% response rate in 78 evaluable patients), advanced breast cancer (53% response rate in 33 pts without significant chemotherapy for the target progression) and Hodgkin's disease (90% response rate after 4 weekly courses in 31 pts). Thus extensive pharmacological studies and ongoing clinical studies confirm that chemical modifications of the catharantine moiety of vinca alcaloid can lead to active agents with broader spectrum of activity and easily manageable side effects.
Cisplatin is one of the best available cytotoxic agents particularly in testicular, ovarian and head and neck cancer. However gastrointestinal and renal toxicities preclude greater utilisation. High dose cisplatin (200 mg/m2) has serious neurological side effects. Carboplatin gives the same therapeutic results as cisplatin in ovarian, small cell lung and head and neck cancers with a better tolerance, the main toxicity being haematological. Iproplatin seems to have no advantage over carboplatin. New derivates such as diaminocyclo-hexane-platinum seem to be promising in preclinical and phase I studies.
Invasion of the internal mammary lymph nodes is common in tumoral pathology of the breast, but an isolated internal mammary lymphadenopathy occurring long after treatment of the primary tumour is a rare event. The authors report one case and discuss the prognostic and therapeutic factors involved.
We report a large kindred in which palmoplantar keratoderma occurred in association with breast or ovarian cancer or both. This kindred consisted of 61 members of four generations. Thirty-five individuals had palmoplantar keratoderma, including eight women who also had breast or ovarian cancer or both. Five of the six women with breast cancer and both the women with ovarian cancer have died. The proband presented with a yellowish, uniform hyperkeratosis surrounded by a red border covering the entire surface of the palms and soles. Light microscopic examination showed features of epidermolytic hyperkeratosis, and ultrastructural examination revealed the typical markers for this entity, cytolysis and clumps of keratin filaments. This kindred is the first, to our knowledge, to have an association of epidermolytic hyperkeratosis and internal malignancy.
Eleven patients who had advanced cancer of the cervix were treated with combination chemotherapy containing Cisplatin as a primary treatment. The cases were: 3 stage II B N+, 2 stage III not involving the bladder, 3 stage III involving the bladder and 3 stage IV. The response rate was 40% with 6 patients responding. The response was better than 50% in 3 and there were 5 failures. In the 6 patients where the treatment was helpful, 2 could have extended surgery whereas the others had follow-up radiotherapy without developing urinary fistulae. Just as it to be found in the literature, it was not possible to pick out prognostic criteria for sensitivity to chemotherapy. A protocol for treatment is suggested, starting with a therapeutic test of chemotherapy. If this is successful it should be followed by extended surgery or radiotherapy. It if is not successful, conventional treatment with radiotherapy will be undertaken. It is essential to carry out multicentre studies in future to find out whether this attitude is going to be successful.
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