Mogens Blichert-Toft

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

PURPOSEnRisk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments.nnnPATIENTS AND METHODSnThe 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%).nnnRESULTSnThere 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).nnnCONCLUSIONnAge 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.

Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values.

Oestrogen receptor concentrations were measured in primary tumours of 291 postmenopausal breast cancer patients with high risk of recurrence. These patients were a subset of the 1650 patients participating in the Danish Breast Cancer Cooperative Groups trial of adjuvant treatment with tamoxifen (30 mg daily for one year). A cut-off point of 10 fmol/mg cytosol protein and the use of a Cox proportional hazards model distinguished between patients with long recurrence-free survivals and those with early recurrent disease. The use of this model also showed that patients with an oestrogen-receptor content below 100 fmol/mg did not benefit from the endocrine therapy, while those with concentrations above 100 fmol/mg had a significantly longer recurrence-free survival. This finding is consistent with the response of advanced breast cancer to endocrine treatment.

Lobular Carcinoma In Situ of the Female Breast: Short-Term Results of a Prospective Nationwide Study

In a Danish nationwide prospective study of in situ carcinoma of the breast, 112 women with ductal carcinoma in situ, treated with excision only, were registered from 1982 to 1987. Within a median follow-up of 53 months, a crude recurrence rate of 22% (25 cases) was found, of which five cases recurred as invasive carcinomas and 20 cases as in situ carcinomas. The histopathologic review included a single-parameter analysis of histological growth pattern, size of lesion, nuclear size, presence of comedonecrosis, and subhistologic type. A strong inter-relationship was found for histological growth pattern, nuclear size, and comedonecrosis. These parameters were also significantly related to recurrence. Cases that had clinical symptoms had a high recurrence rate as compared with cases that were discovered by mammography only or incidentally.In a Danish nationwide prospective study of in situ carcinomas and atypical lesions of the breast, 88 women, comprising 69 patients with lobular carcinoma in situ (LCIS) and 19 patients with combined lobular and ductal carcinoma in situ (LCIS + DCIS), were accrued from 1982 through 1987. All cases were treated with excision only. Within a median follow-up time of 61 months, a recurrence rate of 17% (15 cases) was found, excluding nine cases of refinding of LCIS. No contralateral recurrences occurred. The recurrences were in eight cases invasive carcinomas (IC), in six cases LCIS + DCIS, and in one case DCIS alone. The recurrence rates among cases of LCIS and of LCIS + DCIS were not significantly different. The histopathological review included an estimate of the number of lobules with LCIS and nuclear size, both of which were significantly related to recurrence. The risk of developing IC was calculated to be increased by a factor 11 as compared with the reference population.

Patient's and Doctor's Delay in Primary Breast Cancer: Prognostic implications

In a study of 7,608 patients with primary breast cancer patients and doctors delay were examined in relation to age, tumour size, grade of anaplasia, and number of positive lymph nodes. The delays were arbitrarily divided into the following intervals: Short (0-14 days), intermediate (15-60 days) and long (> 60 days). The well-established patient and tumour characteristics were shown to have prognostic significance. Similarly the delays showed significant influence on survival. A long patients delay was associated with an unfavourable outcome, as compared with a short delay. On the contrary, the prognosis was superior for patients with a long doctors delay compared to those with a short doctors delay. Overall, when corrected for age, the prognostic value of delay in terms of mortality increased by 24% for a long patients delay compared to a shorter and by 13% for a short doctors delay compared to a longer. This indicates that doctors are capable of distinguishing between more and less aggressive malignancies. The study also suggests that all sources of delays should be kept at a minimum.

Treatment Morbidity Associated with the Management of the Axilla in Breast-Conserving Therapy

The purpose of this study was to determine the impact of surgery and radiotherapy on late morbidity associated with the management of the axilla in breast cancer patients. Two hundred and sixty-six patients from a randomized breast conservation trial (DBCG-82TM protocol) were called in for a single follow-up interview and clinical examination of several functional outcome measures after a median of 6.6 years (3.5-10.5). All the patients were treated with lumpectomy and axillary dissection, followed by external beam radiotherapy to the residual breast. High-risk patients were given additional radiation to the regional lymph nodes plus adjuvant systemic treatment. Twenty-eight patients (11%) had arm edema (> or = 2 cm), which was associated with the extent of axillary node dissection as well as with age and radiotherapy (relative risk, RR = 4.5 (1.8-11.2, p = 0.001)). Impaired shoulder movement of any degree (7%) was associated with radiotherapy (RR = 4.0 (1.5-13.8, p = 0.007)) and advanced age (p = 0.002), while the extent of axillary dissection as described by the number of nodes retrieved was the only factor that predicted pain on logistic regression analysis (p = 0.02). A moderate to severe change in arm/shoulder strength and working ability was observed in 7% and 5% of patients, respectively, but no independent predisposing factor was discerned for these endpoints. It is concluded that the level of late functional morbidity several years after breast-conserving treatment is relatively low and clearly relates to age, extension of surgery, irradiation of the axilla or a combination of these factors, depending on the specific clinical outcome measure.

Cosmetic outcome and breast morbidity in breast-conserving treatment: Results from the Danish DBCG-82TM national randomized trial in breast cancer

A total of 266 recurrence-free breast cancer patients from the randomized DBCG-82TM breast conservation trial were called in for a follow-up investigation to study the impact of surgical and radiation treatment factors on the cosmetic and functional outcome after breast conservation. The patients were interviewed and examined after a median follow-up time of 6.6 years, and 194 of them (73%) regarded the cosmetic result as excellent or good. M orbidity assessments showed that breast fibrosis, skin telangiectasia, and breast retraction were significantly associated with a less satisfactory cosmetic result. On univariate analysis, it was found that treatment with a direct anterior electron field produced more morbidity and inferior cosmetic outcomes compared with tangential photon treatment, while increasing breast size was associated with increased breast retraction and breast fibrosis. Treatment characteristics that emerged as independent prognostic factors of a poor cosmetic outcome on multivariate analysis were the use of a direct anterior electron field (OR =2.15, CI 1.25-3.70) and adjuvant systemic therapy (OR =2.13, 1.22-3.71). A significant but relatively low level of concordance was found between the patients and the clinicians evaluations of cosmetic results but self-assessments of breast morbidity and psychological distress were significantly related to the observed treatment-induced side effects after breast-conserving treatment, indicating that subjective perceptions and observations as reported by the patients are relevant for the identification of treatment factors that impact on normal tissue reactions.

Anti-estrogen treatment of postmenopausal breast cancer patients with high risk of recurrence: 72 months of life-table analysis and steroid hormone receptor status

AbstractThe role of anti-estrogen treatment of postmenopausal breast cancer patients with high risk of recurrent disease is evaluated in a nationwide, prospective, randomized trial conducted by the Danish Breast Cancer Group. After total mastectomy and postoperative radiotherapy, 829 patients were randomized to treatment with tamoxifen (RT + TAM) for 1 year and 821 were randomized to no further therapy (RT). The recurrence-free survival (RFS) after 72 months of life-table analysis is 44% in the RT + TAM treated group, and 40% in the RT group (p=0.0003). Survival is 51% in both treatment groups (p=0.53). The data have been further analyzed with respect to prognostic factors such as age, degree of anaplasia, tumor size, and positive nodes. The RFS is lower in all subsets of patients treated with RT + TAM, but is only significant in patients 50–59 years of age, with tumors of anaplasia grade I, with tumors less than 5 cm, or with 4 or more positive lymph nodes.nEstrogen receptor concentrations were measured in a subset of 291 of these patients. A cut-off limit of 10 fmol/mg cytosol protein and the use of a Cox proportional hazards model distinguished between patients with long RFS and those with early recurrent disease. Patients with an estrogen receptor content below 100 fmol/mg did not benefit from the endocrine therapy, while those with concentrations above 100 fmol/mg had a significantly longer RFS. Progesterone receptor determinations were performed in 12% of the patients. Progesterone receptor-positive patients had a lower rate of recurrence when treated with RT + TAM compared to the receptor-positive patients in the RT group (p=0.017).RésuméLe rôle du traitement anti-oestrogénique du cancer du sein opéré après la ménopause chez les malades à hauts risques de récidive a été soumis à une étude prospective randomisée sur le plan national par le groupe Danois dEtude du Cancer du Sein. Cette étude comporte dune part 829 malades qui après mastectomie totale et radiothérapie postopératoire ont été traitées par le tamoxifen (RT + TAM) pendant un an et dautre part 821 malades qui nont pas été soumises à un traitement complémentaire (RT). Labsence de récidive après 3 ans a été de 44% dans le premier groupe et de 40% dans le second. Dans les deux groupes le taux de la survie à 5 ans a été de 51% (p=0.53). Le pronostic basé sur les données rassemblées a été étudié en fonction de plusieurs facteurs: âge, degré danaplasie, volume de la tumeur, envahissement ganglionnaire. Le taux dabsence de récidive à 3 ans a été plus bas chez les malades traitées par lassociation radiothérapie et tamoxifen mais il na de valeur significative que chez les malades âgées de 50 à 59 ans, présentant des tumeurs dont lanaplasie est de stade I, le volume est inférieur à 5 cm et lenvahissement concerne 4 ganglions ou plus.La concentration oestrogénique a été dosée chez 291 de ces malades. La limite de 10 fmol/mg cytosol protéine et lemploi du modèle des risques proportionnels Cox ont permis la distinction entre malades à hauts risques de récidive à 3 ans et les autres. Les malades dont le pouvoir récepteur oestrogénique est inférieur à 100 fmol/mg ne tirent aucun bénéfice du traitement endocrinien contrairement à ceux dont le pouvoir est supérieur. Le pouvoir récepteur progestéronique a été étudié chez 12% des malades. Celles qui ont un pouvoir positif ont un taux de récidive moins élevé quand elles sont traitées par RT + TAM par rapport à celles qui sont traitées seulement par RT (p=0.017).ResumenLa evaluación del valor del tratamiento antiestrógeno en pacientes postmenopáusicas con cáncer de seno con alto riesgo de enfermedad recurrente fue realizada en un ensayo nacional prospectivo y aleatorizado conducido por el Grupo Danés de Cáncer de Seno. Después de haber sido sometidas a mastectomía total y radioterapia postoperatoria, 829 pacientes fueron asignadas en forma aleatoria a tratamiento con Tamoxifén (RT + TAM) por 1 año, y 821 no recibieron tratamiento adicional (RT). La sobrevida libre de recurrencia (SLR) a los 72 meses es de 44% en el grupo RT + TAM, y de 40% en el grupo RT (p=0.003). La supervivencia global es de 51% en ambos grupos (p =0.53). Los datos han sido analizados con respecto a factores de pronóstico, incluyendo edad, grado de anaplasia, tamańo del tumor y ganglios positivos. La SLR es mayor en los subgrupos de pacientes tratadas con RT + TAM, pero es de significación sólo en los grupos de edad entre 50 y 59 años con tumores de anaplasia grado I, de tamaño menor de 5 cm y con 4 o más ganglios linfáticos positivos. Aún cuando se presentaron menos metastasis locales y distantes en las pacientes tratadas con RT + TAM, no se logró un aumento en la supervivencia global y aún en aquellos subgrupos de pacientes con las más significativas prolongaciones de la SLR no se pudo demostrar aumento de la supervivencia.La concentración de receptores de estrógeno fue medida en un subgrupo de 291 de las pacientes. Un límite bajo de 10 fmol/mg de proteína citosólica, distingue a las pacientes con prolongada SLR de aquellas con enfermedad recurrente temprana. Las pacientes con contenidos de receptores de estrógenos por debajo de 100 fmol/mg no derivaron beneficio de la terapia endocrina mientras aquellas con concentraciones superiores a 100 fmol/mg exhibieron una SLR significativamente más prolongada. Determinaciones de receptores de progesterona fueron realizadas en el 12% de las pacientes. Las pacientes con receptores de progesterona positivos tuvieron una menor tasa de recurrencia con el regimen RT + TAM que las pacientes con receptores de progesterona positivos manejadas con RT solamente (p=0.017).En conclusión, la terapia adyuvante con TAM aumenta la SLR en pacientes postmenopáusicas con cáncer mamario de alto riesgo. La eficacia está significativamente correlacionada con la edad de las pacientes y con ciertas características histopatológicas y bioquímicas de los tumores. El valor pronóstico de las determinaciones de RE se logra al emplear un límite bajo en la positividad RE el cual esencialmente sirve para distinguir los tumores RE negativos de los RE positivos. El valor de predicción de las determinaciones de RE y de RPg en cuanto al efecto de la terapia adyuvante parece depender sólo de las concentraciones de RE y RPg en el tejido tumoral, puesto que las más bajas tasas de recurrencia se presentan en pacientes con las más altas concentraciones.

Comparison of the surgical procedures for breast conserving treatment of early breast cancer in seven EORTC centres

The aim of this study was to develop a standardised surgical report for breast-conserving procedures, supporting the systematic documentation of the different aspects of the surgery. The surgical procedure for tumourectomy and axillary clearance was translated into a series of steps that could be quantitatively documented. This description was submitted twice to a group of surgeons from different departments to ensure that all steps that are considered to have relevance for outcome were included and that no superfluous data were collected. After two corrective phases, a first test format was developed. Between February 1993 and May 1994, seven surgical departments, participating in EORTC trials, completed this questionnaire for a number of their patients. The data collected related to general information on the department, the tumour excision itself, the axillary dissection and, in a later phase, on pathology. 269 questionnaires (264 tumour excisions, 259 axillary dissections and 189 pathology reports) were collected and analysed. Even though the participating departments were involved in a single trial on breast-conserving surgery and had previously developed regular contacts about the practical aspects of treatment, many differences were detected. In general, variations were found in the waiting time between treatment prescription and execution, experience of the surgeon, duration of the procedure, and the use of prophylactic antibiotics. Also, in the practical execution of the procedure, major variations in the type of incision, width of tumour excision, closure of the breast tissue and skin, the use of frozen sections and the extent of the axillary dissection were found. The most relevant differences and their possible consequences are discussed. It has been proven possible and feasible to document quantitatively a surgical procedure. The fact that within a group of surgeons participating in the same clinical trials, many differences in the surgical techniques are observed, stresses the need to reach a consensus on a stricter set of guidelines for breast-conserving procedures and their documentation, especially when conducting clinical trials.

Effects of gastric resection and vagotomy on blood and bone mineral content

This investigation evaluates the effects of the Billroth II and I gastric resections and of vagotomy on blood and bone minerals in comparable groups of male patients with peptic ulcer who had no other potentially demineralizing conditions. The series includes 153 patients divided into 3 subgroups according to the type of gastric operation that had been carried out on an average of 5 years earlier (range 1–10 years).A definite trend towards hypocalcemia (p < 0.001) and a modest loss of bone mineral as judged by photon absorptiometry (p < 0.05) occurred in the groups subjected to gastric resection, while changes of statistical significance were not observed following vagotomy. Significant hypomagnesemia, hypophosphatemia, or hyperphosphatasia did not occur in any group. The observations in the vagotomy group suggest that the amount of gastric acid secreted may be unimportant for the maintenance of blood and bone mineral normality. We were unable to establish the true nature of the bone disease that follows gastric resection. On the other hand, there was no substantial evidence indicating that osteomalacia was the only disorder involved.We conclude that in patients without conditions predisposing to disturbed mineral metabolism, none of the surgical procedures evaluated in this study seem to carry an appreciable risk of bone demineralization of clinical importance. With regard to mineral metabolism, vagotomy is preferable to gastric resection.RésuméNous avons étudié les effets des gastrectomies type Billroth II et I et de la vagotomie sur la composition ionique sanguine et la minéralisation osseuse. Létude a porté sur 153 patients de sexe mâle, opérés pour ulcère gastroduodénal et ne présentant aucune autre affection pouvant entraîner une déminéralisation, divisés en 3 groupes selon le type dopération gastrique réalisée. Les gastrectomies et vagotomies avaient été faites 1–10 ans auparavant (moyenne 5 ans). Dans le groupe des gastrectomies, on trouve une nette tendance à lhypocalcémie (p < 0.001) et, aux mesures par absorption photonique, une déminéralisation osseuse modérée (p < 0.05). Le groupe des vagotomisés ne révèle aucune altération significative.Dans les 3 groupes étudiés, il ny a pas dhypomagnésiémie, dhypophosphatémie ni daugmentation des phosphatases. Les observations faites dans le groupe des vagotomisés suggèrent que limportance de la sécrétion gastrique dacide na guère dinfluence sur les ions sanguins et la minéralisation osseuse. Nous navons pu préciser la nature exacte de la maladie osseuse qui apparait après gastrectomie. Mais rien nindique quelle consiste uniquement en ostéomalacie.En conclusion, aucune des opérations étudiées ne semble créer un risque de perturbation du métabolisme minéral ayant quelque importance clinique, chez les malades qui nont aucune autre affection prédisposante à cet égard. En ce qui concerne le métabolisme minéral, la vagotomie doit être préférée à la gastrectomie.

EFFECT OF SELECTIVE GOITRE RESECTION ON ABSENT THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE IN IDIOPATHIC EUTHYROID GOITRES

Absent thyrotrophin (TSH) response to thyrotrophin releasing hormone (TRH) was found in ten of fifty consecutive nodular goitrous patients who were clinically and biochemically euthyroid. These ten patients together with a reference group engaging fifty‐eight healthy individuals matched for sex, age, and geographic region form the basis of the present study. Patients with autonomously functioning single adenomata were excluded from the investigation. In the patient group, values of serum thyroxine (T4), free T4‐index, and serum TSH did not differ significantly from those recorded in the reference group, whereas serum triiodothyronine was found to be significantly higher in the patients, although within the normal range. After selective resection of the goitre, the TSH responsiveness to TRH recovered completely. Routine indices of thyroid function, however, demonstrated no major deviation from pre‐operative levels. During a follow‐up period of 1 year, no systematic alterations were recorded in TSH response to TRH nor in the thyroid function tests, indicating maintenance of euthyroidism with restored normality within the pituitary‐thyroid axis. The present study lends support to the view that increasing functional autonomy apparently is a common trend in goitre evolution in a non‐endemic area.