Advanced breast cancer: a randomized study of doxorubicin or mitoxantrone in combination with cyclophosphamide and vincristine.

BACKGROUND: Drug selection for the treatment of advanced breast cancer is based on both efficacy and toxicity. Combination chemotherapy produces higher response rates than single agents, of which doxorubicin is the most active. This study compares efficacy and toxicity of the drugs doxorubicin and mitoxantrone when used as part of a 3 drug combination. Doxorubicin is the most active agent, but also one of the most toxic, and in this study was compared, in a 3-drug combination, with mitoxantrone with the aim of achieving comparable efficancy with reduced toxicity. PATIENTS AND METHODS: 110 patients with advanced breast cancer previously untreated by chemotherapy were randomized to receive cyclophosphamide and vincristine, together with either doxorubicin 50 mg/m2 i.v. (VAC) or mitoxantrone 10 mg/m2 (VNC) for up to 6 cycles. RESULTS: Of 53 eligible patients randomized to VAC, the overall response rate was 55% (CR rate 17%), while of 55 patients randomized to VNC the overall response rate was 42% (CR rate 7%). The difference is not statistically significant (p = 0.07), but there was a trend towards a higher response rate to VAC in patients aged less than 60, those with nodal and soft tissue disease, and those with 2 or more sites of disease. The principal difference in toxicity was reduced alopecia in favour of VNC. However there was also an increased number of deaths within the first cycle in patients randomized to VAC. There were no differences in survival, relapse free interval, or freedom from progression between the two arms. CONCLUSIONS: Both VAC and VNC are effective regimens in advanced breast cancer. While the confidence limits in this study mean the response rate advantages of VAC could have arisen by chance, younger patients with adverse prognostic factors may warrant consideration of the VAC regimen.

Expression of the p53 gene and presence of serum autoantibodies in ovarian cancer: correlation with differentiation.

A study was carried out to assess the prognostic significance of significance of p53 expression in ovarian tumors. Archival material from 105 ovarian cancer biopsies was examined for the presence of the p53 protein by an immunoperoxidase technique using the cell-mediated immune (CMI) antibody. Employing a 3-point scale for intensity and the proportion of malignant cells positive, 26% of cases had a score of 4 to 6, 19% were 1 to 3, and 55% were negative. There was no correlation with response to therapy or survival at a median follow-up of 6 years, but a higher score was found to correlate with poor tumor differentiation (Spearman rank: p = 0.03). In a more recent series of 38 ovarian cancer patients, serum autoantibodies to the p53 protein were detected in 29% of cases by an ELISA technique compared with 1 out of 73 normal control women. In 19 of these cases, both serum and malignant tissues were negative, while in 7 of the 11 cases with positive sera, the tissue was also found to contain detectable p53 protein. We conclude that tissue expression of p53 in ovarian tumors is associated with poor histological differentiation and the presence of detectable serum autoantibodies.

Can patients wash during radiotherapy to the breast or chest wall? A randomized controlled trial.

A total of 99 patients receiving adjuvant radiotherapy to the breast or chest wall were randomized to one of three washing policies: (1) not washing, (2) washing with water alone, and (3) washing with soap and water. Fifty-three of the patients were treated without the use of bolus, and 46 patients were treated using bolus for 10 to 15 of the 20 treatment fractions. Approximately half of the patients randomized to washing were tattooed. Subjective and objective measurements of acute skin reactions were found to be less in the two groups randomized to washing. There was little difference between the two washing groups. These findings were the same whether or not bolus was used. It is concluded that washing of the skin should be encouraged in patients undergoing radiotherapy associated with low skin doses.

Radiation-induced cell death by chromatin loss. A model to explain the shape of low-linear-energy-transfer cell survival curves.

A model is proposed which relates reproductive death of cells caused by radiation to loss of chromatin at cell division. This loss of chromatin can occur through chromosomal deletions or through the formation of asymmetrical chromosomal exchanges. It is proposed that smaller doses of radiation produce fewer chromatin breaks, which are more likely to be accurately repaired, compared with larger doses. Consequently, smaller doses of radiation are less efficient in causing cell death, leading to a shoulder on the cell survival curve. Experimental evidence supports this model, and the fit between the derived formula and experimental cell survival curves is good. The derived formula approximates to the linear-quadratic equation at low doses of radiation.

Sequential chemotherapy, surgery and radiotherapy in locally advanced breast cancer.

Thirty-seven patients with locally advanced breast cancer, 86% of whom had skin involvement, were treated with three to six cycles of vincristine 1.4 mg m-2, doxorubicin 40 mg m-2 and cyclophosphamide 600 mg m-2. A complete response rate of 19%, and overall response rate of 61% were achieved. Fourteen patients had received a trial of hormone therapy, but no patient had been given prior cytotoxic chemotherapy or radiation therapy. In no case was chemotherapy discontinued on account of toxicity. In patients with partial remission where gross disease more than 3 cm remained, mastectomy (10 patients) or local excision (five patients), was carried out increasing the complete remission rate to 49%. Thirty-two patients then received 45 Gy in 24 days to the breast and regional lymphatics with a further 12 Gy boost to the tumour site. The overall response rate achieved was 86% of the 37 patients, with a total, complete response rate of 76%. The median time to relapse in the 28 complete responders was 17 months. Local palliation, defined as absence of pain, ulceration or an enlarging mass was achieved in 92% of the total number of patients, and the projected local palliation rate at 2 years by life table analysis was 60%. Only 50% of the 10 N3 patients were alive at 1 year, compared to 93% of the 27 N0-N2 patients (P less than 0.05). The overall survival in the entire group at 2 years was 50%. This is an effective and tolerable combined modality approach for the control of local disease in a subgroup of breast cancer patients with complex management problems.

Psychological effects of day case surgery compared with inpatient surgery.

Short term psychological disturbance in 70 children undergoing minor surgery was compared in two randomly allocated groups by means of questionnaires answered by their parents. Significantly less psychological disturbance was reported in children undergoing day case surgery compared with children admitted on the day before and discharged on the day after surgery. Children who had day case surgery were less often reported to require extra attention in the first week after discharge home, and at three months after operation these children were less often said to be still affected by their hospital stay. It is concluded that a reduced psychological upset can now be added to the other arguments in favour of day case surgery in children.

Aluminum in the environment and human health.

The review of over 800 references on aluminum (Al) published since the mid-fifties covers the occurrence of Al in soil, air, water, plants and food products, as well as air and water pollution problems. In addition, the existing quality criteria, the biology and toxicology of Al, and the therapeutic and medical uses are presented. It is concluded that absorption and retention or accumulation of Al in humans occurs at lower levels of intake than had been assumed formerly. However, levels of 5 to 50 times the normal daily intake do not appear to interfere with other metabolic processes. The adverse effects of Al reported in the more recent years resulted from the inhalation or ingestion of Al in concentrations many times greater than the amounts present under normal circumstances. As in the past, there is still no need for concern by the public or producers of Al or its products concerning hazards to human health derived from well established and extensively used products.