J.A. van Dongen

Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer

A (modified) radical mastectomy (RM) was compared with breast-conserving therapy (BCT) in stage I and stage II breast cancer patients. Treatment of the study arm comprised lumpectomy, axillary clearance and radiotherapy to the breast (50 Gy in 5 weeks external irradiation and a boost with iridium implant of 25 Gy). 902 patients were included. There were 734 TNM stage II patients. Patients with microscopically incomplete excision of the tumour were not excluded. After a median follow-up of 6 years, overall survival and local recurrence rates do not differ significantly between the two study arms. Actuarial survival at 8 years was 73% after RM and 71% after BCT; actuarial local recurrence at 8 years was 9% and 15%, respectively. In the mastectomy group tumour size did not affect local relapse, but after BCT the incidence of local recurrences was higher for tumours of 2-5 cm (16%) than for smaller tumours (7%) (at 8 years, P = 0.08). Results of salvage treatment for local recurrence so far were similar in both the BCT and the mastectomy group.

The Impact of tumor size and histology on local control after breast-conserving therapy

To investigate possible contraindications for breast-conserving therapy (BCT) a retrospective clinicopathological study was carried out in 585 patients treated conservatively in The Netherlands Cancer Institute from 1979 to 1984. The local recurrence rate in the breast was 2% at 6 years and was similar in stages I and II breast cancer. Invasive cancer with extensive ductal carcinoma in situ (DCIS) component appeared to be the only main prognostic factor when local failure in the breast was considered. A multivariate analysis revealed that tumor size, microscopically incomplete excision of the primary tumor and age did not have a significant influence on local control alone, when this was corrected for extensive DCIS. When breast and axillary recurrences were taken together, age and extensive DCIS component appeared to be two independent prognostic factors according to a multivariate analysis. Especially patients younger than 40 years with an extensive DCIS component had a higher locoregional recurrence rate.

Prognosis after Treatment for Loco-regional Recurrence after Mastectomy or Breast Conserving Therapy in Two Randomised Trials (EORTC 10801 and DBCG-82TM)

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

Should tamoxifen be a primary treatment choice for elderly breast cancer patients with locoregional disease

SummaryTo determine the efficacy of tamoxifen as primary treatment for elderly breast cancer patients with locoregional disease, the medical records of 85 patients of 75 years and older were reviewed. The median follow-up was 28 months (range 3–97 mo). Complete remission occurred in twelve (14.1%) patients. All of these patients remained in remission until death or closing date of the study. Twenty (23.5%) patients responded with a partial remission; 5 of them subsequently developed tumor progression. Thirteen (15.3%) patients developed initial tumor progression and 39 (45.9%) had disease stabilisation. Nineteen of this latter group subsequently developed tumor progression. Out of 37 (43.5%) patients with tumor progression, 14 patients were salvaged by surgery (n = 13) or radiotherapy (n = 1). Until the closing date of the study, disease could not be controlled by secondary treatment in 12 patients who subsequently died of breast cancer. Twenty-two of the 37 patients were unfit for surgical treatment at progression, of whom 14 were operable at diagnosis. The actuarial 5-year observed survival rate was 40% for the whole patient group.Conclusions: Although some patients (14.1%) managed to maintain a long lasting complete remission, caution should be preserved in using tamoxifen as first-line treatment, because of the high risk of treatment failures. As long as factors can not be identified to predict which subgroups of patients will respond to tamoxifen with a remission lasting for their life-time, tamoxifen may only provide an acceptable alternative for elderly breast cancer patients who are too frail or are unwilling to undergo surgery or radiotherapy. For elderly patients in good physical condition, primary treatment by tamoxifen only delays definitive surgical treatment.

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

In 14 consecutive patients with recurrent melanoma of the lower limb a total of 35 biopsies were taken at the end of perfusion treatment to assess melphalan tissue concentrations in tumour, skin/subcutis and muscle tissue. In tumour tissue (n = 12) the mean melphalan concentration was 6.8 micrograms g-1, which was significantly higher than that of healthy skin/subcutis (3.2 micrograms g-1; n = 10), but equal to that of muscle tissue (6.5 micrograms g-1; n = 13). The correlation between melphalan concentration in the tissues and the concentration in the perfusate was studied. The latter was assessed in the form of melphalan peak concentration and the area under the curve (AUC0-->60) of the melphalan concentration-time curve. Tumour concentration proved to be correlated linearly with AUC0-->60 (R = 0.6, P = 0.002) and muscle concentration with melphalan peak concentration (R = 0.8, P = 0.04). There was no relation between skin/subcutis concentrations and the perfusate parameters. Further research is warranted to study the relationship between melphalan tissue concentration, tumour response and regional toxicity.

A retrospective comparative study evaluating the results of a single-perfusion versus double-perfusion schedule with melphalan in patients with recurrent melanoma of the lower limb

Background. Forty‐two patients with measurable recurrent melanoma of the lower limb were treated according to a double‐perfusion schedule.

Changes in use of breast-conserving therapy in years 1978-2000.

The treatment of breast cancer patients has changed rapidly in the past decade, but empirical data at local and national level are scarce. Predicting the consequences of screening for primary treatment is consequently difficult. The aim of this analysis of records on admissions to hospital of women with breast cancer and/or for breast surgery (1975-90) together with a survey of all Dutch radiotherapy departments (1986-88) is to show the change in breast-conserving therapy and other primary treatment before the start of breast cancer screening in The Netherlands. There was a modest increase in breast-conserving therapy after 1981, coinciding with the first publication on its trial, followed by a sharp increase between 1985 and 1990, after the second publication. At the end of that 5 year period, 36% of all women with newly diagnosed invasive breast cancer underwent this type of surgery. Breast-conserving surgery is always followed by radiotherapy, but there has been a clear reduction in post-operative radiation after mastectomy. The percentage of breast-conserving therapy is at present higher in The Netherlands than in the USA. Implementing the Dutch screening programme will result in a maximum increase in breast-conserving therapy at national level of 34%, which stabilises at +21%, or a 50% maximum increase at local level. The number of women treated by mastectomy will ultimately decrease by 9%. Given the rapidity of change towards the use of breast-conserving surgery, which is enhanced by screening, recent information will be needed in predicting capacity and assessing whether screen-detected women are treated adequately.

Evaluation of routine pre-operative bone scintigraphy in patients with breast cancer

Abstract A prospective study on bone scanning was undertaken in patients with a clinical operable breast carcinoma to investigate its use in the staging of these patients. From 90 patients with a proven breast carcinoma, stages T 1 , T 2 , N 0 , N 1a , the pre-operative whole body skeletal scintigraphy was positive in 7 cases. Four of these could be excluded because other reasons than metastases could be demonstrated to be the cause of the positive scan. So in only 3 cases ( 3·4% ) the scan was positive, suggesting bone metastases. These lesions could, up to now in no way be proven to be metastases. The final percentage of pre-operative detection of bone metastasis after a longer follow up period may therefore even be less than 3·4% . We therefore decided to omit routine pre-operative bone scanning in patients with a breast carcinoma stages T 1 , T 2 , N 0 , N 1a .

The prognostic significance of the axillary apex biopsy in clinically operable breast cancer.

To evaluate the prognostic significance of the axillary apex biopsy and its impact on clinical practice, a retrospective analysis was performed in 875 patients with clinically operable breast cancer who underwent this procedure from 1977 to 1985 (165 TNM stage I; 512 TNM stage II; 198 TNM stage IIIA). Apex biopsy is performed as a staging procedure. Apex biopsy positive patients are treated by radiotherapy alone, while apex biopsy negative patients are treated with breast conserving therapy or mastectomy, both including complete axillary dissection. The apex biopsy was tumour positive in 4% of TNM stage I patients; 17% of stage II patients and 40% of stage IIIA patients. Among patients with clinically node-negative disease, the apex biopsy was positive in 12%; in patients with palpable suspected lymph nodes this figure was 45%. Actuarial 8 y survival rates for patients with stage I, II and III disease and a negative apex biopsy were 83, 70 and 50%, respectively. The corresponding figures for patients with a positive apex biopsy were 60, 28 and 14%. In a multivariate analysis, a positive apex biopsy, clinical N classification and T classification were independent prognostic factors for survival (P < 0.0001). We conclude that a positive apex biopsy is rare in clinical stage I breast cancer, and that in patients with TNM stage II and III disease the procedure is an important tool to assess prognosis pre-operatively.

Regional Isolated Limb Perfusion in Patients with Malignant Melanoma

In this overview the Amsterdam/Rotterdam ‘controlled’ normothermic (tissue temperatures 37-38 °C) perfusion technique is described. The benefit of the widely used so-called ‘mild’ hyperthermia (39-40°C) is queried. A plea is made to report acute regional toxicity after perfusion according to Wieberdink’s grading system for uniformity. Perfusion has a well-established role in the treatment of locally inoperable melanoma. As an adjunct to surgery, benefit has also been shown in resectable stage II–III recurrent melanoma. For stage I primary melanoma the results of the ongoing EORTC/WHO adjuvant trials are eagerly awaited. In measurable disease an overall response rate of about 80% (with equal proportions of complete and partial remissions) can be obtained by single normothermic or ‘mild’ hyperthermic perfusion. Perfusion strategies that have been investigated to improve the complete response rate are discussed: the application of other cytostatics than melphalan, the role of repeat perfusions, perfusion with melphalan at borderline ‘true’ hyperthermic temperatures (40.5-42°C), sequential perfusion applying ‘true’ hyperthermia (42-43°C) and melphalan separately, and perfusion with the combination of rTNF-alpha, Inter-feron-gamma and melphalan. The ideal of a 100% complete remission rate has been approached in several perfusion strategies but the duration of remission is still rather short. The main issue for the immediate future will therefore be prolongation of the limb recurrence-free interval.