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Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer: a phase I/II study

Article Abstract:

Unfortunately, there are many ways in which cancer chemotherapy can fail. One of the more significant is the development of multiple drug resistance, or MDR. Under the onslaught of cytotoxic drugs, many of the tumor cells die, but a few live cells are left to grow again. These cells may, however, be genetic variants that are more resistant to chemotherapy, and indeed, may be resistant to a number of different drugs, including active chemotherapeutic agents such as doxorubicin, etoposide, and vincristine. The development of MDR is thought to be related to the increase in expression of a membrane protein called P-glycoprotein, the product of the mdr-1 gene. Laboratory investigations have shown that various chemical compounds can neutralize the drug resistance in these cells; these chemicals, called response modifiers (RM), include substances such as verapamil, a calcium-channel blocker, and tamoxifen, and antiestrogen derivative of triparanol. Since these compounds are already approved for other uses, it seems natural to examine their effects on the treatment of small cell lung cancer with chemotherapeutic agents. Rather than perform the experimental trials on patients who had already developed a large population of resistant cells due to previous treatment failure, it was decided to begin the trials with previously untreated subjects, who might have only a small number of multiply resistant cells at the time of treatment. A consecutive series of 58 patients with small cell lung cancer were treated with doxorubicin, vincristine, and etoposide. Three days before each course of chemotherapy, the patients were started on daily doses of the response modifiers verapamil and tamoxifen. Patients with tumors that had metastasized to the brain, residual disease, or symptomatic metastases were given radiation treatment. No toxic effects directly attributable to the RMs were observed, but the toxic effects of the chemotherapeutic drugs were considerable. Bone marrow suppression was the most common side effect, and 24 percent of the patients had severe infections. The median survival of the patients was 46 weeks. Previously reported studies have found survival times of 18 and 24 weeks under similar conditions. A side finding was that a 40 percent response rate could be achieved using cyclophosphamide and cisplatin to treat the patients who failed initial chemotherapy, which suggests only a partial cross-resistance between the two sets of drugs. The results suggest that the inclusion of verapamil and tamoxifen are of significant benefit in the chemotherapy of small-cell lung cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Genetic aspects, Drug resistance, Lung cancer, Small cell, Small cell lung cancer, Verapamil

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Endocrine versus endocrine plus five-drug chemotherapy in postmenopausal women with stage II estrogen receptor-positive breast cancer

Article Abstract:

In a previous study, 311 women who had undergone a modified radical mastectomy for stage II breast cancer were treated with combinations of tamoxifen (T), an anti-estrogen compound, cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (F) which are chemotherapeutic agents, and the biological response modifier bacillus Calmette-Guerin (BCG). The results demonstrated that BCG had no beneficial effect. In addition, it was clear that the chemotherapeutic drugs (C,M, and F) alone were less effective than the CMF plus tamoxifen (T). Unfortunately, there was no opportunity to compare the effectiveness of tamoxifen alone with the effectiveness of tamoxifen and CMF. In this study, 94 postmenopausal women with stage II breast cancer, who had undergone either radical or modified radical mastectomy, were randomly assigned to receive either tamoxifen alone, 40 mg daily for three years, or the three year tamoxifen regimen plus a six-month chemotherapeutic treatment consisting of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP). The patients' tumors had the estrogen receptor on their cells (estrogen receptor-positive breast cancer), which is an indicator that the cells will be responsive to endocrine therapy, that is, the anti-estrogen compound tamoxifen. The median follow-up was 55 months. As would be anticipated, the group receiving T+CMFVP experienced significantly more side effects than the group given only T. The combined treatment group also showed significantly greater survival throughout the period of the study and there did not seem to be any increase in breast cancer recurrence after three years, suggesting that this might be an appropriate treatment period. Previous studies, though not precisely comparable, have suggested that one or two years of therapy may not be sufficient. Recurrences have been observed in stage IV patients after 5 to 10 years, indicating that breast cancer may remain suppressed for long periods. Although the median 55-month follow-up indicates a beneficial effect of treatment with T+CMFVP, further observations will be necessary to determine if these benefits are long-lasting. (Consumer Summary produced by Reliance Medical Information, Inc.)

Care and treatment, Postmenopausal women

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Intraarterial induction chemotherapy in locally advanced Stage III breast cancer

Article Abstract:

Radical mastectomy has been abandoned by some practitioners as a treatment of Stage I and Stage II breast cancer in favor of more conservative therapies, although controversy exists as to the relative risks and benefits of this approach. Radical breast surgery has also been largely abandoned as initial treatment for patients with advanced Stage III breast cancer, but for different reasons. In advanced Stage III cancer, in which the entire breast is likely to be involved, surgery may result in a healed wound contaminated with cancer tissue. This effect could certainly compound the patient's difficulties. The initial use of chemotherapy in such cases has a dual advantage; the size and extent of the primary tumor may be reduced, rendering it more amenable to surgery, and the tiny, undetected metastases, which are almost certainly present, may be attacked before they are large enough to cause symptoms. The use of direct intraarterial infusion to deliver chemotherapeutic drugs was evaluated in 27 patients with advanced Stage III breast cancer. After implantation of the cannula into one of several possible arteries, blue dye was injected. If the breast turned blue, the cannulation was clearly successful. A cyclic infusion of doxorubicin, 5-fluorouracil, vincristine, and methotrexate was administered. Chemotherapy was followed by radiotherapy or surgery. Of the 22 patients with noninflammatory cancer, 16 were apparently cured at 5 years. Of the 22 patients, however, 6 had refused mastectomy; 3 of these enjoyed apparent cure at 5 years in contrast to 11 of 16 who chose mastectomy. (One of the 11 patients reported as apparently cured was also reported to have died of her cancer a year later.) The fate of the patients with inflammatory cancer was worse; only one of five patients achieved local control of the tumor. This same patient is the only member of the group to survive and is disease-free at five years. The results show that the intraarterial infusion of chemotherapeutic agents directly into the breast may offer promise as a treatment technique for advanced Stage III breast cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Methods, Surgery, Identification and classification, Injections, Intra-arterial, Intra-arterial injections

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