Knud West Andersen

Differences in Risk Factors for Local and Distant Recurrence After Breast-Conserving Therapy or Mastectomy for Stage I and II Breast Cancer: Pooled Results of Two Large European Randomized Trials

PURPOSE Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01). CONCLUSION Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

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.

On the Relaxation of the Hard—Sphere Rayleigh and Lorentz Gas

As part of a study of the relaxation of nonequilibrium systems, the (translational) relaxation of a hardsphere Rayleigh and Lorentz gas is investigated. From a detailed analysis of the collision dynamics an exact expression is derived for the kernel A (x | x′) of the collision integral which gives the probability per unit time for a change of the reduced kinetic energy from x′ to x during a binary collision between a subsystem and a heat bath particle. A master equation, i.e., a linearized Boltzmann equation, incorporating this kernel is then formulated to represent the time variation of the distribution function of the subsystem particles. Making use of the special property of this kernel that it is a strongly peaked function around x—x′=0 for both the Rayleigh and Lorentz gas, a technique is developed for transforming this integral master equation into differential Fokker—Planck equations consistent in the order of the expansion parameter λ, the ratio of the mass of the heat bath particles to the subsys...

Time since childbirth and prognosis in primary breast cancer: population based study

Abstract Objective: To investigate whether time since birth of last child was of prognostic importance in women with primary breast cancer. Design: Retrospective cohort study based on a population based database of breast cancer diagnoses with detailed information on tumour characteristics, treatment regimens, reproductive factors, and vital status. Setting: Denmark. Subjects: 5652 women with primary breast cancer aged 45 years or less at the time of diagnosis. Main outcome measures: 5 and 10 year survival; relative risk of dying. Results: Women diagnosed in the first 2 years after last childbirth had a crude 5 year survival of 58.7% and 10 year survival of 46.1% compared with 78.4% and 66.0% for women whose last childbirth was more than 2 years before their diagnosis. After adjustment for age, reproductive factors, and stage of disease (tumour size, axillary nodal status, and histological grading), a diagnosis sooner than 2 years since last childbirth was significantly associated with a poor survival (relative risk 1.58, 95% confidence interval 1.24 to 2.02) compared with women who gave birth more than 5 years previously. Further analyses showed that the effect was not modified by age at diagnosis, tumour size, and nodal status. Conclusion: A diagnosis of breast cancer less than 2 years after having given birth is associated with a particularly poor survival irrespective of the stage of disease at debut. Therefore, a recent pregnancy should be regarded as a negative prognostic factor and should be considered in counselling these patients and in the decisions regarding adjuvant treatment. Key messages A childbirth close to subsequent diagnosis of breast cancer has a negative effect on the womans cancer prognosis The negative effect of recent childbirth is not affected by age at diagnosis, nodal status, and tumour size The negative effect is found both in patients who receive adjuvant treatment and those who do not Childbirth history should be taken into account when counselling young women with breast cancer

Evidence of a castration-mediated effect of adjuvant cytotoxic chemotherapy in premenopausal breast cancer.

This prospective randomized trial, conducted by the Danish Breast Cancer Cooperative Group, is the largest study, so far, of adjuvant chemotherapy in premenopausal breast cancer. The trial is unique in that it is nationwide and based on a nonselected population of patients, and is the only adjuvant trial studying the effect of cyclophosphamide monotherapy. After total mastectomy with axillary node sampling, followed by local radiotherapy, 1,032 pre- and perimenopausal women with operable breast cancer were randomized to observation alone, or to adjuvant chemotherapy for 1 year with either cyclophosphamide monotherapy or with a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). As of January 1987, median follow-up was 68 months. From early on both cyclophosphamide alone and CMF were found to improve recurrence-free survival (RFS) significantly and to a similar degree (P = .0001). However, an overall survival advantage did not become evident until 5 years after the start of treatment. So far, this advantage appears to be more pronounced in CMF (P = .0065) than in cyclophosphamide-only patients (P = .08). Thus, the study confirms the findings of the National Surgical Adjuvant Breast Project (NSABP) and Milan trials that adjuvant chemotherapy prolongs the survival of premenopausal women with early breast cancer. A retrospective analysis revealed that, in contrast with CMF, cyclophosphamide alone did not improve RFS significantly in subsets of patients without amenorrhea, with estrogen-receptor (ER) negative tumors, and with tumors of low histological differentiation. Assuming that cyclophosphamide alone is a less tumoricidal treatment than CMF, these findings suggest that the effect of adjuvant cytotoxic chemotherapy is mediated partly through chemical castration, and partly through a purely cytotoxic effect.

Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen.

SummaryThe anti-estrogen tamoxifen is the prevalent endocrine treatment in postmenopausal breast cancer patients. However, nothing is known about the long-term effects of the drug on the skeleton as assessed by the occurrence of fractures.We investigated the occurrence of fractures of the femur in patients from a Danish Breast Cancer Cooperative Group (DBCG) trial initiated in 1977 by a linkage of data from the Danish National Registry of Patients with data from the DBCG registry. 1716 postmenopausal women with high-risk breast cancer were randomized to local radiotherapy with or without tamoxifen, 30 mg daily for 1 year.Fifty-one patients in the control group had one femoral fracture and 64 tamoxifen treated patients had one femoral fracture. Eleven patients in the control group had one trochanteric fracture compared to 27 patients in the tamoxifen group (logrank = 5.28, P = 0.022; hazard ratio = 2.12, 95% CL 1.12, 4.01).The results could not be explained by a longer survival in the tamoxifen group nor by bone metastases with pathological fractures.In conclusion, our study suggests that tamoxifen does not seem to offer protection against fractures in old age and may even increase the risk of fractures at particular sites. This hypothesis needs to be disproved or confirmed in other trials.

Stage and pattern of metastases in patients with breast cancer

This study compares the pattern of metastases in 228 patients with initial stage I and 635 patients with initial stage II breast cancer. All these patients had recurrence within a median time of follow-up of 4.9 years (range 2.0-7.0 years). All patients were initially mastectomized, and staging was based on histopathological evaluation of mastectomy specimens. Patients with stage II disease received postoperative radiotherapy; 67% also received systemic adjuvant therapy. Locoregional recurrences were the most common sites of recurrence in stage I, whereas distant metastases occurred more often in stage II patients. Stage II patients had a significantly higher number of metastatic sites than stage I patients. Among patients with a single site of recurrence the frequency of local or regional recurrence was 62% in stage I patients compared to 16% in stage II patients. When correcting for this difference, which was ascribed to the effect of radiotherapy, the number and the distribution of metastatic sites were almost equal in stage I and II patients. The anatomical distribution of metastatic sites in different periods after mastectomy was almost the same in stage I and stage II patients; extraregional lymph node metastases, however, occurred earlier in stage II than in stage I patients. The recurrence-free interval, the survival after recurrence (SAR), and the overall survival were all significantly shorter for stage II than for stage I patients. The reduced SAR for patients with stage II disease hints that tumours of higher stages have a higher rate of progression. The progression time, however, was of the same duration in patients with initial stage I and II breast cancer. The prognostic significance of the classification of patients with breast cancer according to stage does not seem to discriminate tumours with different biological properties with regard to the rate as well as the pattern of dissemination. Postmastectomy follow-up of patients with stage I and II disease should therefore, follow the same guide-lines. Since the anatomical distribution of metastases was the same in different periods after mastectomy, the screening for recurrent disease should not be directed towards any specific sites in certain periods after initial diagnosis.

Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer

SummaryAfter total mastectomy and partial axillary dissection, 805 premenopausal women with stage II breast cancer were randomized to receive postoperative radiotherapy (RT) alone, RT + cyclophosphamide (C) for 12 monthly cycles, or RT + cyclophosphamide/methotrexate/5-fluorouracil (CMF) for 12 monthly cycles. At 3 years actuarial relapse-free survival for RT + C and RT + CMF was significantly better than for RT alone (p = 0.0009 and 0.0001, respectively). There was no significant difference in relapse-free survival between RT + C and RT + CMF.C resulted in more pronounced haematologic toxicity and a higher frequency of amenorrhoea and of alopecia than CMF, while CMF resulted in more pronounced nausea and stomatitis than C.In the preliminary results, C alone may be as effective as CMF in prolonging relapse-free survival in premenopausal women with stage II breast cancer.

Antiestrogen treatment of postmenopausal women with primary high risk breast cancer

SummaryThe role of antiestrogen treatment in high risk postmenopausal patients with primary breast cancer is currently evaluated in a nationwide, prospective randomized trial conducted by the Danish Breast Cancer Cooperative Group. The primary treatment is total mastectomy and radiotherapy. As of February 1, 1982, 720 women were randomized to treatment with tamoxifen (30 mg daily for 1 year) and 691 women were randomized to no further therapy. Life-table analysis after 36 months shows a difference in recurrence rates of 9% (p = 0.19) in favor of the tamoxifen-treated patients. The material has been analyzed with respect to established prognostic factors such as age, degree of anaplasia, tumor size, and number of positive nodes. The rates of recurrent disease are lower in all subsets of patients treated with tamoxifen, but are only statistically significant in patients 50–59 years of age or with 4 or more positive lymph nodes. Regardless of treatment, ER negative patients have a 23% higher recurrence rate than ER positive patients after 18 months of analysis (p = 0.0033); this represents an approximate doubling of risk, and is independent of age, degree of anaplasia, tumor size, or lymph node status. With regard to PgR status, there is 11% higher recurrence rate in the PgR negative than in the PgR positive patients (p = 0.097).

Adjuvant systemic treatment and the pattern of recurrences in patients with breast cancer

The aim was to analyze the impact of adjuvant systemic treatment (AST) on the anatomical distribution, the number, and the temporal relationship of the first metastases in 635 patients (pts) with breast cancer. These patients participated in the prospective studies of AST of the Danish Breast Cancer Cooperative Group (DBCG) 77-program. All patients had primary high-risk breast cancer (i.e. node positive or local invasion or tumor size greater than 5 cm). The initial treatment was mastectomy with axillary sampling, followed by postoperative radiotherapy. The types of AST and the number of patients with recurrence were: chemotherapy (CT), 134 pts; levamisole (LEV), 96 pts; tamoxifen (TAM), 154 pts. The pattern of recurrence in these patients was compared with the pattern of recurrence in 251 pts who did not receive AST (controls). Although CT reduced the total number of metastatic sites (P = 0.04), the incidence of liver metastases was increased compared to untreated controls (P = 0.02). The median number of metastatic sites was equal in TAM- and LEV-treated pts compared to controls. The incidence of lung metastases was increased in TAM-treated pts (P = 0.03), and LEV-treated pts had a decreased incidence of lymph node (P = 0.01) and pleural recurrences (P = 0.01) compared to controls. The results may suggest that mechanisms of clonal selection during the metastatic process involve differences in sensitivity to antineoplastic treatments of metastases at various anatomical locations.