Eight-year results of a prospective non-randomised study on therapy of small breast cancer. The German Breast Cancer Study Group (GBSG).

In this report, the results of the first controlled clinical trial on breast cancer in Germany, begun in 1983, are presented after a median follow-up of 8 years. Four-year results have been previously published. In pT1 N0 M0 breast cancer, mastectomy as the standard treatment was to be compared with tumorectomy plus radiotherapy to the remaining breast tissue. The study design, originally planned as a comprehensive cohort study including randomised and non-randomised patients, had to be changed into a prospective observation study due to the low randomisation rate. 1036 out of 1119 recruited patients were evaluable. After a median follow-up of 97 months, 237 events (local recurrence, regional recurrence, distant metastases, contralateral breast cancer or death of the patient without previous recurrence) occurred. With the exception of death without recurrence, the events were evenly distributed among the two treatment groups. The 8-year local recurrence rate of the whole patient population is 8.8%. Out of all prognostic factors examined, only tumour size and grade had a significant influence on recurrent disease. Event-free survival decreased in cases with 'uncertain' tumour margins, whereas the width of the margin has no influence on disease recurrence. Based on 151 deaths observed so far, there was no significant difference in overall survival between the two treatment groups. The 8-year results of this study are in accordance with the 4-year results reported previously and with those of other breast-conserving treatment trials. There was no significant difference between the two treatment groups with regard to event-free and overall survival. Incomplete tumorectomy had a negative influence on recurrence.

[Introduction of studies by the German Breast Center Study Group (GBSG)]. / Vorstellung der Studien der German Breast Center Study Group (GBSG).

The GBSG is actually running two studies on breast cancer therapy: GBSG-5 addresses the necessity of radiotherapy following tumor removal, in breast preserving treatment of pT1N0M0 G1 breast cancer. The other question to be answered in a randomised 2- by 2-design is related to the replacement of radiotherapy by a 5-year treatment with tamoxifen. Up till now, 341 patients have been randomised. 200 more patients are needed for a valid study evaluation. GBSG-6 will be activated in fall of this year. It should answer the question whether the addition of systemic therapy to the local treatment of isolated locoregional recurrence will prolong time to further relapse as well as overall survival. According to a prognostic profile derived drom previous studies patients will be randomly allocated to more or less intensive treatment with chemo- and/or hormone therapy.

[Detection of disseminated carcinoma cells in bone marrow and peripheral blood in primary breast cancer with RT/PCR of parathyroid hormone-related protein (PTHrP)]. / Nachweis disseminierter Karzinomzellen im Knochenmark und peripheren Blut beim primären Mammakarzinom mittels RT/PCR des Parathyroid Hormone-related Proteins (PTHrP).

The analysis of tissue specific gene expression by reverse transcription based RT/PCR methods is currently evaluated as a method for the detection of tumor cell dissemination in patients with cancer. Breast cancer tissues express PTHrP and the level of PTHrP expression in the primary tumor correlates with the incidence of metastases in the bone. We applied a RT/PCR assay of PTHrP to detect tumor cells in the mononuclear cell fraction of peripheral blood (pb) and bone marrow (bm) of patients with newly diagnosed breast cancer. PTHrP positivity was found in 18/67 pb and 20/71 bm samples. In a median follow up of 23 months there were 7 metastatic relapses (4 osseous, 2 hepatic, 1 pulmonary) and 9 local relapses in patients with primary lymph node positive breast cancer. The hepatic and pulmonary relapses had been both PTHrP-PCR negative in pb and in bm. Of the 4 patients with metastatic relapses to the bone the samples of bm had been initially negative in all cases, the pb had been positive in 2 cases. Of the 9 patients with local recurrences the pb alone had been positive in 4 patients, 5 patients had been negative in both the pb and the bm. During the period of observation there was no local and metastatic relapse detectable in the group of patients with primary lymph node negative breast cancer. In summary the increased risk for local or systemic relapse would have been predictable by RT/PCR of PTHrP alone in pb in 4 of the 9 local and in 2 of the 7 early metastatic relapses. Further follow-up of the patient cohort analysed is needed to assess the value of the RT/PCR of PTHrP as a prognostic and predictive marker in patients with breast cancer.

[Brief interdisciplinary oncology: a model for ambulatory, multimodal treatment of tumor patients]. / Interdisziplinäre Kurzzeit-Onkologie (IKO): Ein Modell zur ambulanten, multimodalen Behandlung von Tumorpatienten.

Since 10/1994 the Interdisziplinäre Kurzzeit-Onkologie (IKO) is an outpatient department for the treatment of patients with cancer used by the departments of hematology/oncology and surgery. Between 09/1995 and 02/1997, 818 patients received 2024 cytotoxic therapies with neoadjuvant (15%), adjuvant (65%) or palliative (20%) intention-mostly within multicenter clinical studies. Ambulatory operations like removal of lymph nodes for diagnosis or the implantation of venous catheter systems prepared the way for specialized modalities of cancer therapy. The high compliance and consent of patients, combined with better understanding of cancer therapy, resulted in an enhanced quality of life and optimized therapy. Standardization in diagnostics and fast realisation of interdisciplinary treatment schedules lead to reduction of costs and to enhancement of quality and security in cancer therapy.

[Therapy of the small breast carcinoma--generalized conversion to breast-saving treatment in Germany. 8 years results]. / Therapie des Kleinen Mammakarzinoms--flächendeckende Umsetzung der brusterhaltenden Behandlung in der BRD. 8-Jahres-Ergebnisse.

In the prospective nonrandomized observation study "Therapy of Small Breast Cancer", which was the first multicenter trial on breast cancer ever conducted in Germany, mastectomy (303 cases) was compared with breast-preservation therapy (733 cases) in patients with stage pT1N0M0 breast cancer. After a median follow-up of 8 years, there is no difference between the treatment modalities with regard to disease-free and overall survival which compares well with the results of international randomized studies. There is no difference in treatment outcome between centers specialized in the therapy of breast diseases in comparison to less experienced institutions as long as a high standard of treatment performance is guaranteed by reference centers.

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group (GBSG) started a multicenter randomized clinical trial to compare the effectiveness of three versus six cycles of 500 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil (CMF) on day 1 and 8 starting perioperatively with or without tamoxifen (TAM) (3 x 10 mg/d for 2 years). The aim of the trial was to compare recurrence-free and overall survival between the different treatment modalities. PATIENTS AND METHODS: During 5 years, 41 institutions randomized 473 patients (3 x CMF: 145; 3 x CMF + TAM: 93; 6 x CMF 144; 6 x CMF + TAM: 91). Until March 31, 1992, median follow-up time was 56 months with 197 events for disease-free survival and 116 deaths observed. This provides a power of approximately 80% to detect a potential treatment difference corresponding to a relative risk (RR) of 0.67 for recurrence-free survival. Treatment modalities and various patient characteristics were evaluated by means of a multivariate Cox regression analysis. RESULTS: No significant difference in recurrence-free survival was observed with respect to hormonal therapy (RR = 0.75 TAM v no TAM; 95% confidence interval [CI], 0.54 to 1.04; P = .08) as well as duration of chemotherapy (RR = 0.90 of 6 x CMF v 3 x CMF; 95% CI, 0.67 to 1.19; P = .45). Similar results were obtained for overall survival. The multivariate analysis revealed a significant prognostic impact of the number of positive lymph nodes and the progesterone receptor level on recurrence-free survival. Compliance with chemotherapy within the range of 85% to 115% of the target dose was achieved in 94% and 78% of the patients randomized to 3 x CMF and 6 x CMF, respectively. Sufficient compliance with TAM was reported for 141 patients (93%). CONCLUSION: At this stage of follow-up, six courses of CMF are not superior to three courses with respect to recurrence-free survival.

Quality control review for radiotherapy of small breast cancer: analysis of 708 patients in the GBSG I trial. German Breast Study Group (GBSG).

Within six years between November 1983 and December 1989 the German Breast Cancer Study Group (GBSG) conducted a prospective multicenter trial on the treatment of pT1 pN0 M0 breast carcinoma. Out of 1036 eligible patients from 69 hospitals, a total of 733 underwent breast preservation surgery and postoperative radiotherapy. A detailed quality control (QC) screening of 708 available radiotherapy records was performed by the radiotherapy reference center. The following quality control scoring system was used for all radiotherapy variables: Radiotherapy treatment "completely according to study protocol" (QC score = 0); "acceptable protocol deviations" (QC score = 1); "unacceptable protocol violations" (QC score = 2); the "overall QC score" was the worst judgement for any single quality control criterion, while the "total QC score" was the summation of all single quality control scores (range: 0 to 14). 292 (41.2%) patients were treated per protocol; 290 (41.0%) had acceptable protocol deviations; and 126 (17.8%) had unacceptable protocol violations. 107 (84.9%) single violations, 15 (11.9%) combinations of two, three (2.4%) combinations of three, and one (0.8%) combination of four unacceptable violations were observed. 564 (79.4%) patients achieved a total QC score of < or = 2, 124 (17.5%) of 3 to 5, and 20 (2.8%) of > or = 6. The criterion "radiotherapy treatment duration" had the highest rate of protocol violations, 67/708 (9.5%); other quality control criteria with protocol violations were "radiotherapy reference dose" (27 = 3.8%), "radiotherapy treatment initiation" (15 = 2.1%) and "other protocol violations" (33 = 4.7%). No protocol violations were observed for the criterion "target volume coverage". The protocol compliance improved slightly during the conduct of the study. Institutional differences in protocol compliance were observed depending upon the accrual rate, the institutional treatment preference and between academic and non-academic hospitals. After a short median follow-up of 48 months, differences in protocol compliance, i.e. protocol violations, have not resulted in a reduced disease-free survival; however, the final prognostic evaluation of the quality control review may require longer follow-up and eventually different treatment endpoints to be analyzed.

[Initial results of the Project of the German Breast Cancer Study Group on "Breast saving therapy of the small breast cancer"]. / Erste Ergebnisse des Projekts der Deutschen Brustkrebs-Studiengruppe (GBSG) zur "Brusterhaltenden Therapie des kleinen Mammacarcinoms".

In the German Breast Cancer Study Group (GBSG) multicenter trial "Breast preservation in small breast cancer" 1119 patients were accrued over a period of six years. The study was originally designed as a randomized trial which had to be changed into a prospective observation study. A high therapeutic standard was guaranteed by quality control. The univariate analysis of prognostic variables was the first step to a valid treatment comparison. Those factors determined as being significant were combined with the treatment effects in a multivariate analysis. The published results were obtained after a median observation time of four years.

Breast preservation versus mastectomy in early breast cancer--1991 update of the GBSG 1--protocol and prognostic factors. The German Breast Cancer Study Group.

In 1983, the German Breast Cancer Study Group (GBSG), sponsored by the Federal Ministry of Research and Technology, started a prospective multicenter trial on the treatment of early breast cancer (pT1 pN0 M0). This was preceded by a three-year reviewing period because of some novelties of medical, juristical and ethical problems in the FRG. University and, in the majority, community hospitals participated, combining all together 69 different institutions. From 11/1983 to 12/1989, 1112 patients were recruited. From 1036 patients, 733 underwent breast preservation (71%) and 303 mastectomy (29%). The randomization rate was only 6%. In 268 patients (26%) the tumor size was less than or equal to 10 mm, in 765 patients (74%) 11 to 22 mm. In 129 cases, we subdivided the tumor grading II[3] into IIa and IIb. Moreover, the immunohistochemical detection of the transmembrane proteins EGFR, p-185 and p-148 by oncogene overexpression and c-myc oncogene were undertaken in 425 breast cancers. After tumorectomy (or wide excision) and a lower axillary dissection (at least eight lymph nodes) the breast was irradiated up to 50 Gy in 25 fractions. A boost of 12 Gy was given to the tumor bed. The medial located lymph nodes were also irradiated in case of medially or centrally tumors. Quality control was performed by pathological, radiotherapeutic and methodical reference centers. Significant correlations could be demonstrated between receptor status and tumor grading, patient age and grading, and tumor size and grading. The results emphasize the central role of tumor grading among the prognostic factors. Especially the differentiation of the Bloom and Richardson score II into IIa and IIb seems to play an important role. After a median follow-up of 41 months, the frequency of local recurrences (4.4%), regional recurrences (1%) and distant metastases (4.6%) was exactly the same in both treatment groups. In multivariate analysis, only tumor size and tumor grading had a significant impact on disease-free survival. 23 patients with tumor-involved margins had a higher recurrence rate (DFS 62% versus 85% after five years). Without any impact on DFS were the other conventionally evaluated prognostic factors: age, menopausal status, hormone receptor status, histological tumor type, tumor localisation, degree of differentiation, pleomorphism, mitotic index and degree of dissociation. Among the transmembrane proteins EGFR, p-185, p-148 and c-myc, only the impact of p-185 and EGRF positivity on DSF is significant.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapy of small breast cancer: a prospective study on 1036 patients with special emphasis on prognostic factors.

In 1983, The German Breast Cancer Study Group, sponsored by the Federal Ministry of Research and Technology, started a prospective multicenter trial on the treatment of early breast cancer pT1 pN0 M0. Treatment consisted of initial tumorectomy with microscopically free margins and lower axillary dissection. After conformation of a pT1 pN0-stage, additional treatment was either mastectomy or adjuvant radiotherapy (50 Gy in 25 fractions to the entire breast plus 12 Gy electron boost). In medially located tumors, the parasternal and supraclavicular area was also irradiated with 50 Gy. A randomization between both treatment modalities was initially planned but was not feasible and abandoned. Nearly all patients were treated according to their own choice. From November 1983 through December 1989, 1119 patients were recruited. Eighty-three were excluded from the protocol. Out of the remaining 1036 patients, 733 (71%) underwent breast preservation and 303 (29%) mastectomy. A detailed pathohistological examination of all tumorectomy specimens was performed in a pathologic reference center. Oncogen overexpression was evaluated by immunohistological detection of the transmembrane protein p-185 (corresponding to c-erb-B2) in 425 cases. After a median follow-up of 48 months, the frequency of local recurrences (4.7%), regional recurrences (1%), and distant metastases (5.4%) was the same in the breast preservation group and the mastectomy group. The 3-year disease-free survival was 90% after breast preservation and 88% after mastectomy (p = 0.21). In the breast preserving group, 24 patients with microscopically involved margins had a poorer disease-free survival than the study group (75% vs 90% after 3 years). The width of the margins had no impact on prognosis. Other prognostic factors in an univariate and multivariate analysis were tumor size and tumor grade. Age, menopausal status, hormone receptor status, histological tumor type, and treatment (mastectomy vs breast preservation) were not significant. P-185-expression was dependent on tumor grade and was the strongest prognostic factor in an univariate and multivariate analysis (p less than 0.001). The results emphasize the central role of tumor grade for prognosis and suggest the independent prognostic significance of the c-erb-B2 oncogen (corresponding to p-185) in pN0-patients.

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

[Surgical therapy of breast cancer]. / Chirurgische Therapie des Mammakarzinoms.

The surgeon's leading role which he plays in the changing concept of primary breast cancer treatment is described. To apply breast conserving therapy a number of prerequisites must be fulfilled. As compared to mastectomy, there are still a number of problems connected with this treatment modality. Therefore, it remains doubtful whether the latter can already be regarded as standard treatment. For the future, reducing breast cancer mortality as well as treatment individualization remain the major goals.

[Indications, technique, results and value of breast saving surgery in breast cancer]. / Indikation, Technik, Ergebnisse und Stellenwert der brusterhaltenden Chirurgie beim Mammakarzinom.

Breast preservation is by no means a standard treatment modality for breast cancer. An increasing number of unsatisfactory results have been observed despite the fulfillment of requirements necessary for adequate treatment. Excellent surgical technique is a solid basis for good cosmetic result. According to the interim analysis of the German breast preservation study a tumor biopsy with a small margin of healthy tissue together with a lower axillary dissection can be considered a sufficient surgical procedure. The relationship between tumor size and size of the breast is one of the most important factors determining contraindications for breast preservation. Adequate instruction of the patient still remains a major problem for most doctors. If the patient is properly informed about the operation quality of life is not substantially altered after mastectomy and breast reconstruction compared with breast preservation therapy.

Therapy of early breast cancer: preliminary results of the German Breast Cancer Study.

The German Breast Cancer Study Group has a large, homogeneous patient population with pT1 pN0 breast cancers who have undergone a detailed pathohistological work-up and uniform treatment. Seventy institutions take part in this study, mostly community hospitals. All pathologic specimens are reviewed by the Pathology Reference Center. Moreover, in order to improve the quality of radiation therapy, all dosimetric data, radiation protocols, and localization, and verification films are reviewed by the Radiotherapeutic Study Centre. By January 31, 1988, 762 patients had been recruited. At the moment, after an admittedly short follow-up period for the majority of our patients, there is no evidence of differences between the two treatment arms concerning the incidence of local and distant recurrences, contralateral breast cancers, and other malignancies. However, the study demonstrates several unresolved problems, mainly the collection of follow-up data which can arise when many institutions especially community hospitals and general practitioners, are involved in a prospective trial.

Acute renal failure following hyperthermic isolation perfusion of the left leg.

This is the case report of a 37-year-old female who underwent primary excision of a malignant melanoma on the left foot as well as an inguinal lymphnode dissection in May 1983. In January 1984 a satellitosis on the same foot was treated with an isolation perfusion which had to be repeated in December of the same year due to secondary satellitosis. For the first perfusion, Alkeran 80 mg was used with a temperature of up to 41.4 degrees C, whereas Cis-Platinum 20 mg/l and Eldesine 0.3 mg/l were used for the second perfusion, with a maximum temperature in the tumor area of 39.0 degrees C. On the first postoperative day, significant edema of the left leg accompanied by severe pain was noticed. This was followed by an increase of the serum creatinine to 2.2 mg % two days later. Despite the immediate inducement of a forced diuresis, renal function deteriorated during the following days with serum creatinine going up to 4.8 % and CK to 14800 U/L. After a forced diuresis of two weeks' duration, the laboratory parameters slowly went back to normal. As a consequence of this complication we analyzed the influence of hyperthermic isolation perfusion on five patients with regard to muscular damage and its influence on renal failure. During perfusion we observed myoglobinemia which subsided within 36 hours. This slope was paralleled by CK values. A discrete myoglobinuria which was observed in two patients disappeared within 36 hours after perfusion. No rise of creatinine could be found. The changes described above were not influenced by cytostatic medication (Alkeran versus Cis-Platinum and Eldesine). In addition, none of the cases showed a leakage of over 16%. The case of acute renal failure was apparently caused by increased rhabdomyolysis as a consequence of the second hyperthermic perfusion.

[Breast-saving therapy--a safe alternative in primary treatment of breast cancer?]. / Die brusterhaltende Therapie--eine sichere Alternative bei der Primärbehandlung des Mammacarcinoms?

Since Fisher's publication in March 1985 conservative breast cancer treatment is viewed ever more uncritically. In order to avoid local recurrence this therapeutic modality can only be justified in connection with radiotherapy the negative effects of which are often neglected. Thoroughly competent surgical technique, careful pathological work-up of the tumor material and a computerized radiation planning as a prerequisite for a homogeneous radiotherapy of the breast are necessary to perform conservative breast cancer therapy. Legal-ethical aspects make it imperative to inform the patient about the advantages and disadvantages of conservative versus radical therapy. The realization of conservative breast cancer treatment on a broad basis is, at present, only justifiable under study conditions.

Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer.

In a long-term follow-up study, prolactin levels were measured in 149 patients with advanced metastatic breast cancer. Control groups included 221 patients with primary operable breast cancer and 150 women with benign breast disease. Hyperprolactinemia (greater than 1,000 mIU/I; HYPRL) occurs in 44% of patients with metastatic breast cancer in the course of the disease (p less than 0.001 compared to patients with non-metastatic disease). HYPRL is associated with progressive breast cancer in 88% of cases. In patients experiencing several episodes of disease remission and relapse, incidence of HYPRL increases with each relapse. Prolactin blood levels return to normal if hyperprolactinemic patients experience remission after chemotherapy. Patients expressing HYPRL have a shorter survival time after mastectomy when compared to patients who never developed HYPRL (154/89 months, p = 0.01). It is concluded that HYPRL is of prognostic significance and a reliable indicator of progressive disease in advanced metastatic breast cancer.