H.T. Ford

Bone marrow micrometastases in primary breast cancer : prognostic significance after 6 years follow-up

Using an antiserum to epithelial membrane antigen we have screened multiple bone marrow aspirates from 350 patients with primary breast cancer taken at the time of initial surgery. 89 (25%) patients were found to have micrometastases and their presence was related to pathological size (P less than 0.01), the presence of peritumoral vascular invasion (P less than 0.001), and positive lymph nodes (P less than 0.005) but not menopausal status. At a median follow-up of 76 months (range 34-108) 107 patients had relapsed with distant metastases. 48% (43 of 89) of these patients had micrometastases initially compared with 25% (64 of 261) who did not (P less than 0.005). The test predicts for relapse in bone (P less than 0.01) and other distant sites excluding bone (P less than 0.001) and is associated with a shorter overall survival (P less than 0.005). We conclude that the detection of micrometastases signals a high likelihood of early relapse and decreased survival in breast cancer.

PREVENTION OF EMESIS IN PATIENTS RECEIVING CYTOTOXIC DRUGS BY GR38032F, A SELECTIVE 5-HT3 RECEPTOR ANTAGONIST

15 patients receiving cytotoxic drugs (other than cisplatin) that had previously produced nausea and vomiting refractory to first-line antiemetics were given a selective 5-HT3 receptor antagonist (GR38032F), 4 mg intravenously and 4 mg orally, immediately before chemotherapy, the oral dose being repeated 5 and 10 h later. Nausea, vomiting, and side-effects were recorded for the ensuing 24 h. The 15 patients received a total of thirty-one courses of chemotherapy. Only 1 patient vomited. The only adverse events were dryness of the mouth in 1 patient, mild sedation in 1, and diarrhoea in 1, and these were not clearly drug related.

INCREASED DETECTION OF MAMMARY CARCINOMA CELLS IN MARROW SMEARS USING ANTISERA TO EPITHELIAL MEMBRANE ANTIGEN

We have developed a technique for the immunocytochemical staining of marrow smears using antiserum to epithelial membrane antigen (EMA). This membrane component is confined to, but widely distributed in, epithelial tissues and tumours derived from them, and is strongly expressed by infiltrating breast carcinoma cells. Marrow aspirates from patients with both early and metastatic breast cancer have been examined, and the results of immunocytochemical staining compared with conventional cytology and histology. Staining with antiserum to EMA enabled us to detect small numbers of carcinoma cells, and increased the yield of positive samples. Furthermore, using this technique, we found malignant cells in the marrow of patients with primary breast cancer with no other evidence of metastatic disease. Thus immunocytochemical staining for EMA may be of value in the detection of micrometastases in patients with primary breast carcinoma.

FAILURE OF CHEMOTHERAPY TO PROLONG SURVIVAL IN A GROUP OF PATIENTS WITH METASTATIC BREAST CANCER

Overall survival of patients with primary breast cancer has not improved in the past ten years, despite increasing use of multiple-drug chemotherapy for treatment of metastases. Furthermore, there has been no improvement in survival from first metastasis, and survival may even have been shortened in some patients given chemotherapy. Chemotherapy probably does prolong survival in some patients, and further studies should be undertaken to identify these patients in advance.

PROSPECTIVE RANDOMISED TRIAL OF TAMOXIFEN VERSUS SURGERY IN ELDERLY PATIENTS WITH BREAST CANCER

116 patients aged 70 or over who were judged to have surgically resectable cancer of the breast were prospectively randomised to tamoxifen 20 mg daily or surgical resection. At a median follow-up of three years, local relapse or progression was seen in 15 (25%) of 60 patients in the tamoxifen group and 21 (37.5%) of 56 in the surgical arm. Distant metastases occurred in 8 (13%) in the tamoxifen group and in 10 (18%) in the surgical arm. There were 13 deaths in the tamoxifen group and 11 in the surgical arm, of which 8 and 9, respectively, were attributable to breast cancer. Disease-free survival did not differ between the groups.

PREVENTION OF ISOPHOSPHAMIDE-INDUCED UROTHELIAL TOXICITY WITH 2-MERCAPTOETHANE SULPHONATE SODIUM (MESNUM) IN PATIENTS WITH ADVANCED CARCINOMA

In 8 patients receiving intravenous isophosphamide 2 g/m2 at 2-week intervals for advanced bronchogenic carcinoma the protective effect of 2-mercaptoethane sulphonate sodium (mesnum) against isophosphamide-induced urothelial toxicity was tested in a single-blind crossover trial. With isophosphamide alone, 7 of the 8 patients developed either haematuria or symptoms of bladder irritation; when mesnum was given in addition, only 1 patient had microhaematuria and frequency, and this was in association with a urinary-tract infection. 5 patients then received fifteen courses of isophosphamide in increasing doses of 4 to 8 g/m2 i.v. with mesnum. In contrast to previous experience with isophosphamide at this high dosage, frank haematuria was never seen, microhaematuria was seen after only three courses, and mild dysuria after only one course. Pharmacokinetic studies showed that mesnum did not interfere with the metabolism of isophosphoramide or its active anti-tumour metabolite, isophosphoramide mustard. Mesnum therefore enhances the therapeutic ratio of isophosphamide and may thereby increase its clinical efficacy.

The influence of extent and local management on the outcome of radiotherapy for brain metastases

The results of cranial irradiation for brain metastases in 164 consecutive patients have been reviewed to evaluate a policy of localized high dose irradiation for solitary metastases. Fifty of the 164 patients receiving whole brain irradiation (35 Gy in 15 daily fractions) were selected for boosts delivering 15 Gy in 8 daily fractions to the site of solitary deposits. No difference in overall survival or the incidence of death from progressive brain metastases was seen between the patients receiving a boost and those who did not. Overall median survival was 112 days with 62% of patients dying from metastatic disease outside the brain. Factors associated with increased survival were early response to radiotherapy and, in breast cancer patients, a disease-free interval of 2 years. Palliation of presenting symptoms was achieved in 86% of patients at 3 weeks from starting radiotherapy. It is concluded that whereas whole brain irradiation results in useful symptom control, there is no advantage for high dose treatment in the majority of patients with solitary metastases even in the absence of metastatic disease elsewhere.

Assessment of Response of Bone Metastases to Systemic Treatment in Patients With Breast Cancer

Seventy‐one patients with breast cancer and bone metastases, together with other assessable sites of disease, were monitored by radiologic skeletal survey, bone scanning, pain charts, bone marrow aspirate, serum calcium, alkaline phosphatase and urine hydroxyproline/creatinine ratio. On the basis of UICC criteria of response in nonosseous sites, 37 were classed as responders and 34 as nonresponders. Responding patients with osteolytic disease frequently showed sclerosis, but only at 6–8 months, whereas patients with mixed lytic/sclerotic or sclerotic metastases frequently showed no change or further sclerosis. Nonresponders most frequently showed progressive lysis. Bone scanning showed clear evidence of improvement or deterioration in 7/21 responders and 8/23 nonresponders who showed no definite evidence of progression or response on skeletal radiography. Pain assessment was also useful in these patients. Neither the bone marrow aspirate nor other biochemical tests were useful in assessing response to therapy. This study concludes that bone scanning and pain assessment are both useful in assessment of response of bone metastases to treatment in some patients and incorporation into a standard criteria of response is recommended.

DETECTION OF BREAST CARCINOMA METASTASES IN BONE: RELATIVE MERITS OF X-RAYS AND SKELETAL SCINTIGRAPHY

Of 1116 patients receiving primary treatment for breast carcinoma at the Royal Marsden Hospital since 1976, 651 had an abnormal bone scintigram either at primary diagnosis (378) or on subsequent follow-up (273) and 167 developed radiographically detectable bone metastases (21 at the time of primary diagnosis). Comparison of bone scintigrams and X-rays showed that scintigraphy was an inaccurate localiser of existing radiographic detectable metastases. If X-rays alone are used to detect bone metastases a limited examination with five plates will detect metastases with 92% accuracy. After primary surgery, routine X-ray screening for bone metastases is not necessary since it is possible to identify patients at risk on the basis of clinical examination, chest X-ray, and serum alkaline phosphatase and gamma-glutamyl transpeptidase levels.

Factors Affecting Acute Skin Toxicity in Patients Having Breast Irradiation After Conservative Surgery: A Prospective Study of Treatment Practice at the Royal Marsden Hospital

The results are presented of a prospective study of acute skin toxicity in 197 patients with early stage breast cancer, who were treated by conservative surgery and postoperative radiotherapy. We have examined the factors determining the severity of the acute skin reaction with particular reference to the degree of dry or moist desquamation at the completion of treatment. One hundred and ten patients had treatment with radiotherapy alone. The remaining 87 received synchronous chemotherapy with breast irradiation, using either the 3M or the 2M regimen, consisting of mitoxantrone and methotrexate, with (3M) or without Mitomycin-C (2M). Patients were analysed according to both the severity and the site of the skin reaction, age, dose, dose variation across the central outline, treatment technique, beam energy, field separation and breast size. A univariate analysis of these results, which has been presented as an odds ratio of the likelihood of developing a moderate or severe reaction in comparison with those scored as mild, has shown that several factors are associated with an increase in the acute skin reaction. These include the use of the semi-supine technique (odds ratio (OR) = 7.3 (95% CI 3.7-14.6)), beam energy (60Co: 6-10 MV photons OR = 5.9 (95% CI 2.6-13.4)), field separation (> or = 20 cm: < 20 cm OR = 4.1 (95% CI 2.2-7.8)), dose variation across the central outline (> or = 10%: < 10% OR = 9.7 (95% CI 2.6-36.4)), inclusion of the axilla (OR = 4.6 (95% CI 2.4-8.9)), and bust size (bra cup size C and D: A and B OR = 4.6 (95% CI 2.7-11.9)). Using multivariate logistic regression, the technique of radiation delivery and bust size were shown to be independently significant variables affecting acute skin reaction. In view of the high correlation between variables (e.g. radiotherapy technique and beam energy) it is still not possible to specify with definite certainty which is the primary variable causing the skin reaction. However 20/57 (35%) of patients treated by the semisupine technique sustained a severe skin reaction, with > 10% dry or moist desquamation in the treatment field. This compares with only 6/140 (4%) patients treated by the supine method. A possible mechanism by which treatment using the semisupine technique may enhance acute toxicity is discussed. We conclude that there are both treatment and patient related factors that will increase the acute skin reaction after breast irradiation.