Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.

Prognosis of patients with breast cancers up to 1 cm in diameter.

The prognosis of patients with tumours measuring up to 1 cm diameter was examined. 336 patients treated at Guy's Hospital between 1975 and 1994 were reviewed. Of these, 103 (31%) were lymph node-positive, with approximately one third of these having one node involved, one third two to three nodes and one third four nodes or more. A similar proportion of those with palpable and impalpable tumours had axillary node involvement. Patients with axillary node involvement had a significantly worse prognosis and those node-positive patients with impalpable cancers had a significantly worse outcome compared with node-positive palpable cases. When patients were subdivided on a basis of nodal status and age (< or = 50 or > 50), node-positive women aged > 50 fared significantly better than younger women. These data suggest the need to know accurately the axillary nodal status of patients with small breast cancers, whether symptomatic or detected by screening. This knowledge will allow women with curable cancers to be identified together with those who have a worse prognosis and who will be likely to benefit from systemic adjuvant therapy.

Tamoxifen protects against steroid-induced bone loss.

As part of a clinical trial of adjuvant endocrine treatment in postmenopausal women with operable breast cancer serial bone density measurements have been performed by dual photon absorptiometry. Tamoxifen alone was given to 26 women, and 20 received additional prednisolone. By 24 months after entry there was no significant difference between mean bone density of the two groups, nor any significant change from baseline levels. There was a mean gain of 0.46% in the tamoxifen group and 1.95% in those given additional prednisolone. Thus the predicted steroid-induced bone loss was inhibited by tamoxifen. This may be of more general use in prevention of osteoporosis in patients requiring long-term steroid treatment.

Iridium implant treatment without external radiotherapy for operable breast cancer: a pilot study.

A pilot study has been conducted to examine a new approach to the treatment of operable breast carcinoma. 27 patients with tumours measuring up to 4 cm in diameter have been treated by tumourectomy, axillary clearance and high dose iridium-192 implant (55 Gy) without any external beam radiotherapy. This enabled the entire local primary treatment of the breast carcinoma to be given in five days. The technique was compatible with adjuvant chemotherapy for those with involved axillary nodes. Local complications have been few and locoregional control has to date been satisfactory. With a relatively short median follow-up of 27 months, cosmesis was objectively rated as good or excellent in over 80% of cases and subjectively rated good/excellent in 96%. High dose brachytherapy now requires testing in a prospective clinical trial to determine whether it is as effective as standard breast conservation techniques for management of early breast cancer.

Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer.

Serum progesterone and oestradiol levels have been measured in 210 premenopausal women with operable breast cancer on samples taken within 3 days of tumour excision. There was no relation between oestradiol level and time since last menstrual period, nor any effect of oestradiol value on prognosis. However, serum progesterone levels were related to the phase of the cycle as determined by time since last menstrual period. When divided on a basis of levels > 1.5 ng/ml (luteal phase) and < or = 1.5 ng/ml, it was found that there was no difference in survival between the two groups among 117 axillary node negative cases. However, in the 93 patients with positive axillary nodes, higher progesterone levels were associated with significantly better survival. Thus, serum progesterone levels at the time of surgery may affect the prognosis of premenopausal node positive patients with operable breast cancer.

Inadequacy of iridium implant as sole radiation treatment for operable breast cancer.

In order to avoid a prolonged course of external irradiation as part of breast conservation therapy, 27 patients received an iridium implant to the primary tumour bed as sole radiation treatment. Surgery was standardised comprising tumourectomy and axillary clearance. Using a rigid implant afterloading with iridium192 wires, 55 Gy was delivered on a continuous basis over 5 days. After 6 years median follow-up, relapse of cancer within the treated breast has occurred in 10 of the 27 patients (37%). Compared with historical controls treated by similar surgery and iridium192 implant (20 Gy) with external radiotherapy (46 Gy), there was a significantly increased breast relapse rate in those treated by iridium implant alone. However, the incidence of distant metastases and overall survival was similar. Thus, a continuous iridium192 implant delivering 55 Gy in 5 days is not an effective means of achieving local control in patients with operable breast cancer.

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10850 comparing modified radical mastectomy with tumorectomy plus tamoxifen.

We have examined the outcome of older patients with operable breast cancer treated in a randomised trial by either standard surgery or less extensive surgery and tamoxifen. There were 236 participants aged >/=70 years, randomised to either modified radical mastectomy MRM (n=120) or wide local excision (WLE) and tamoxifen (T) 20 mg daily (n=116). Survival curves were estimated using the Kaplan-Meier method and multivariate analyses were performed using Cox's proportional hazards model. Endpoints were survival and time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. No significant difference was seen in terms of progression-free survival, but there were significantly more loco-regional relapses in the WLE+T group. In contrast, there were more distant metastases in the MRM group, but with a similar overall survival in both groups. The results of this trial give cautious support for the use of WLE+T for selected older women.

Assessment of skin dose and its relation to cosmesis in the conservative treatment of early breast cancer.

A conservation technique has been developed for the treatment of early breast cancer which involved removal of the tumor, axillary clearance, tumor site implantation with Iridium-192 wires for a boost dose and subsequent treatment of the breast with radical megavoltage external beam therapy. Although the cosmetic results were satisfactory in the majority of the patients, for some it was rated as fair or poor. One variable factor which could have carried some morbidity was the dose of radiation received by the skin. In 51 patients, doses were measured at several points over the treated breast using Thermoluminescent Dosimetry (TLD) at the time of the iridium implant and during the subsequent external beam therapy. Development of skin pigmentation, oedema, and fibrosis were unrelated to the dose received by the skin but the findings suggested that doses greater than 50 Gy to the skin increased the possibility of late (greater than 24 months) telangiectasia over the boosted area. Treatment of tumors in the lower half of the breast, or in large breasts, was associated with a higher incidence of poor cosmesis. This may have been the result of varying posture on the interstitial dose distribution from the Iridium-192 wires and comparison of dose distribution in both supine and erect positions was carried out.

A new combined approach to the conservative treatment of early breast cancer.

A combined surgical and radiotherapeutic technique is described that aims to: (1) achieve permanent local control of disease; (2) give full information on the histology and biochemistry of the tumor; (3) detail axillary node status; and (4) be compatible with adjuvant endocrine therapy or chemotherapy. This treatment is accomplished with minimal cosmetic defect and, in the majority of patients, with almost total conservation of the breast form. The surgical procedures are carried out during one hospital admission and performed with one anesthetic. No prosthetic replacement or augmentation of the breast is involved.

Follow-up of patients with aspirated breast cysts is necessary.

A review was conducted of 401 women who presented with breast lumps that proved to be cysts by yielding fluid on aspiration. The aim was to determine the proportion of patients with cancers that masqueraded as cysts and to establish whether short-term follow-up was necessary. After the first visit, six patients had biopsies because of a residual mass or a bloodstained aspirate. Of these patients, two were found to have cancer. After the follow-up visit, 20 further biopsies were carried out for presence of a mass, bloodstained fluid, or recurrent fluid, and two more cancers were diagnosed. Of the four patients with malignancy, only one had an intracystic carcinoma, two had necrotic grade 3 ductal carcinomas, and one had a malignant phyllode tumor. These findings underline the value of a single return visit after cyst aspiration.

Toxicity of intra-arterial doxorubicin in locally advanced breast cancer.

Four patients with inoperable, locally advanced breast cancer were treated i.a. with 25-35 mg/m2 doxorubicin given as a 6-h infusion on 2 successive days. In each patient, the catheter was introduced percutaneously via the femoral or brachial artery using local anaesthetic and positioned in the internal mammary artery without complications. However, within 48 h of starting treatment all four patients developed extensive erythema over the chest wall, which progressed to superficial ulceration in one case. Two patients also developed a raised hemidiaphragm and phrenic nerve paralysis that was associated with a pleural effusion in one case. This study closed prematurely because of unacceptable local toxicity; thus, we cannot assess the activity of doxorubicin given in this way. If this approach to local control is to be tested further in locally advanced breast cancer, lower doxorubicin doses should be used, or different drugs selected.

Automatic needle biopsy in the diagnosis of early breast cancer.

An automatic needle biopsy system, Bioptycut, has been evaluated for use in the outpatient biopsy of 107 patients with suspected operable breast cancer. Of the 107 patients, 96 proved to have malignancy. The sensitivity of the test was 65%, and the specificity 100%. Using a fine gauge needle the sensitivity was originally less than that of Trucut biopsy, but improved results were obtained with more experience.

Loco-regional recurrence following mastectomy for early breast carcinoma: efficacy of radiotherapy at the time of recurrence.

This study aims to define the risk factors for loco-regional relapse following mastectomy, and to assess the efficacy of radiotherapy at the time of relapse. To achieve this 272 patients with loco-regional relapse treated at a single institution with modified radical or radical mastectomy were reviewed. Tumour size, axillary node involvement and tumour grade were found to be significant risk factors for loco-regional recurrence of disease. Radiotherapy given at the time of relapse controlled disease in 61% of cases, compared with 34% of patients treated with systemic treatment only. Altogether, 146 (54%) of the 269 evaluable patients with local failure had uncontrolled disease at the same site, either at the time of death or at the date last seen. The result of this retrospective study showed that delayed radiotherapy was effective in controlling the disease in patients with developing loco-regional relapses. However, as adjuvant radiotherapy reduces the incidence of local disease recurrence it should be recommended to patients considered to be at high risk of local relapse following mastectomy; namely those with tumours bigger than 5 cm with four or more positive axillary nodes.

Breast parenchymal patterns in women with bilateral primary breast cancer.

Mammograms were obtained from 44 women aged over 30 years with bilateral primary breast cancer, 60 women with unilateral breast cancer, matched for age and menopausal status with the bilateral cases, and 937 normal women, again all aged over 30 years. The mammograms were classified according to Wolfe's criteria. Both groups of cancer patients were found to have a significantly (p less than 0.05) greater proportion of pre-menopausal women with the DY type of breast parenchymal pattern compared with the normal pre-menopausal women. No association was found between the P2 mammographic pattern and breast cancer. The study failed to show any difference in the distribution of mammographic risk categories in women with bilateral disease and those with unilateral cancers only.

A controlled trial of short-term versus standard axillary drainage after axillary clearance and iridium implant treatment of early breast cancer.

A controlled trial has been conducted to determine the safety of early drain removal after axillary clearance as part of conservation treatment in early breast cancer. A total of 84 patients was entered into the study of whom 41 had the drain removed after 5 days, irrespective of the volume of fluid draining, and 43 had drains removed when fluid was less than 20 ml per day. Of the standard drainage group, 28% required percutaneous aspiration of lymph because of subsequent accumulation, compared with 49% of the short-term drainage group. Early drain removal was not associated with any increase in wound complications nor in cosmetic outcome, but did enable earlier discharge of patients from hospital.

LHRH analogue for treatment of recurrent and refractory mastalgia.

The LHRH analogue Zoladex was used to treat 21 premenopausal women with severe recurrent or refractory breast pain. Severity and pattern of mastalgia, whether cyclical or non-cyclical, was assessed using self-administered record cards. Symptom relief was achieved in 17 (81%) of the patients. This study showed Zoladex to be an effective short-term treatment for refractory and recurrent mastalgia.

Patterns of recurrence in Western and Japanese women with breast cancer.

The patterns of relapse in Western women with breast cancer were compared with women from Japan. The results reported are based on a review of the literature. A significant difference between Japanese and Western women was seen with regard to relapse in bone, lung, and liver as assessed clinically. More Western women had bone metastases, but the incidence of pulmonary and liver metastases was higher in Japanese women. A significant difference between the races was also seen with regard to locoregional recurrence of disease, with Japanese women showing a higher incidence of relapse in the supraclavicular lymph nodes compared to Western women. Postmortem studies showed that although the initial metastatic pattern may differ between Japanese and Western women, at time of death the disease is as widely disseminated in the former as it is in the latter.

Double-blind controlled trial of tamoxifen therapy for mastalgia.

60 patients with severe mastalgia of more than 6 months' duration were randomly selected for treatment with either tamoxifen 20 mg daily or placebo for 3 months. As measured by linear analogue scoring, pain relief was achieved in 22/31 (71%) of those receiving tamoxifen and 11/29 (38%) of those taking placebo. Patients who did not respond to the first course of treatment were allocated to the alternative treatment for 3 months. Pain control was achieved in 8/12 (75%) of those receiving tamoxifen and 2/6 (33%) of those receiving placebo. The commonest side-effects were hot flushes (27% of patients receiving tamoxifen and 11% of those receiving placebo) and vaginal discharge (17% tamoxifen, 7% placebo). Side-effects caused 6 patients in each group to discontinue treatment. Tamoxifen is of value in the management of severe cyclical and non-cyclical mastalgia, and relief can be achieved without undue side-effects in the majority of patients.

Paget's disease of the nipple: a ten year review including clinical, pathological, and immunohistochemical findings.

Thirty-five women with biopsy-proven Paget's disease of the nipple were treated over a 10 year period at the Breast Cancer Unit, Guy's Hospital. Twenty-four (69%) patients had Paget's disease without a palpable mass in the breast; eleven (31%) presented with a palpable mass and Paget's disease of the nipple. Definitive treatment consisted of modified radical mastectomy in 32 patients, radiotherapy only in 2, and one patient had no definitive treatment. All 11 patients with Paget's disease and an associated lump proved to have invasive ductal carcinoma; five also had associated positive axillary nodes. Nine of the 23 patients with nipple changes only, treated by mastectomy, also had invasive carcinoma; three of these had positive axillary nodes. The remaining 14 patients with nipple changes only were found to have in situ ductal carcinoma, which was extensive in the majority of cases. In 13 cases, histological sections of the nipple were examined by immunohistochemical staining which showed that the Paget's cells expressed a keratin phenotype that was specifically characteristic of simple epithelial cells as seen in glandular epithelium. This was quite unrelated to the normal keratin phenotype of the surrounding skin keratinocytes. Clinical, pathological, and immunohistochemical data suggest a mammary origin of the abnormal cells in Paget's disease of the nipple. Mastectomy appears to be the treatment of choice.