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Background: Cutaneous recurrences of breast cancer may cause considerable discomfort due to ulceration, oozing, and pain and can also be difficult to treat. Electrochemotherapy is a localised anticancer treatment using electric pulses to make cell membranes permeable, augmenting uptake of chemotherapeutic drugs, and thus enabling highly efficient tumour cell kill. This is the first systematic investigation of electrochemotherapy for larger cutaneous recurrences of breast cancer., Patients and Methods: We conducted a phase II trial for patients with cutaneous recurrences where no further treatment options were available. Primary endpoint was objective response evaluated by clinical examination. Secondary endpoints included response evaluated by PET/CT, change in lung diffusion capacity, patient reported symptoms, and distress related to bodily appearance. Treatment consisted of bleomycin injection followed by application of electric pulses., Results: Seventeen heavily pre-treated patients received electrochemotherapy. Twelve patients were evaluable (follow-up > 8 weeks). CT showed four (33%) patients achieving over 50% tumour volume reduction, clinical examination showed one CR and one PR (OR 17%). Symptomatic relief included decreasing exudates, odour, and bleeding. Treatment was well tolerated; the main side effect was post-treatment pain., Conclusion: This first phase II study indicates that electrochemotherapy is a promising treatment alternative for cutaneous recurrences of breast cancer.

Purpose and Patients: During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment., Results: During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75-1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur., Conclusion: The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.

Introduction: A cohort of premenopausal patients with primary hormone receptor positive breast cancer was prospectively identified to be eligible for the DBCG 89B trial. We perform a long-term follow-up and evaluate the external validity of the trial., Material and Methods: Following registration in a population-based registry, patients were invited to be randomized to ovarian ablation (OA) versus nine courses of three-weekly cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The same procedures were used in all patients, including report forms, central review, querying, and analysis of data. Multivariate analysis was used to adjust for differences in base-line characteristics., Results: Participation in the randomization varied according to center and time period. One thousand six hundred and twenty eight eligible patients were registered and 525 randomized in the DBCG 89B trial. Median estimated follow-up was 9.5 years for disease-free survival and 12.1 years for overall survival. Non-enrolled patients had a disease-free and overall survival similar to randomized patients. Within 5 years of surgery, results were similar following OA and CMF, but disease-free survival was significant inferior with OA more than five years after surgery, adjusted hazard ratio 1.38 (95% CI 1.03 to 1.85; p=0.03). This convened ten years after surgery to an inferior survival with OA, and the adjusted hazard ratio was 2.37 (95% CI 1.43 to 3.91; p<0.01)., Discussion: This prospective cohort study indicates that eligible patients not participating in the DBCG 89B trial had a similar disease-free and overall survival as participants. Survival was similar after OA and CMF in the first ten years, but became inferior in the OA group 10 or more years after surgery.

From January 1, 1990 to December 31, 1994, DBCG conducted a randomised trial in 1 615 postmenopausal women with operable, high-risk, receptor-positive or -unknown breast cancer. The patients were after surgery randomised to Tamoxifen for 1 year (TAM1), Tamoxifen for 2 years (TAM 2) or Tamoxifen for 6 months followed by megestrol acetate for 6 months (TAM/MA). When the preplanned sample size of 1 500 patients was reached it was decided to continue randomisation to TAM1 or TAM2 and the study was finally closed December 31, 1996. With a median follow-up of more than 10 years, there was no difference in disease-free survival (DFS) or overall survival (OS) among the three treatment arms. Similar results were obtained in the original and extended comparisons of Tamoxifen for 1 versus 2 years. A multivariate analysis in the per-protocol treated patients did not show significant differences in hazard ratios for DFS or OS among the three arms. Side-effects were rare but more common in the TAM2 and TAM/MA arms.

This paper describes the procedure of changing from 2D to 3D treatment planning guidelines for post-mastectomy radiotherapy in Denmark. The aim of introducing 3D planning for post-mastectomy radiotherapy was to optimize the target coverage and minimize the dose to the normal tissues. Initially, it was investigated whether it was possible to find a treatment technique alternative to the one recommended by the Danish Breast Cancer Cooperative Group (DBCG). A dosimetric comparison of a combined photon/electron 3-field technique (3F) and a partial wide tangent technique (PWT) was carried out on individual planning CT-scans from seven patients selected to represent a wide range of sizes and shapes of chest walls. The heart dose was lower for PWT than for 3F, however, for both techniques the dose was within the accepted constraints. The lung dose was higher but acceptable for six of the seven patients with PWT. The dose to the internal mammary nodes (IMN) was not satisfactory for five of the seven patients for 3F, whereas only two of the seven patients had a minimum dose lower than 95% of the prescribed dose with PWT. Finally, the dose to the contralateral breast was increased when using PWT compared to 3F. It was concluded that PWT was an appropriate choice of technique for future radiation treatment of post-mastectomy patients. A working group was formed and guidelines for 3D planning were developed during a series of workshops where radiation oncologists and physicists from all radiotherapy centres participated. This work also included a definition of the tissue structures needed to be outlined on the planning CT-scan. The work was initiated in 2003 and the guidelines were approved by the DBCG Radiotherapy Committee in 2006. The first of January 2007 the 3D guidelines had been fully implemented in five of the seven radiotherapy centres.

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. Morbidity 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 clinician's 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.

From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged < or = 56 years with primary operable breast cancer and > or = 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n = 36), fatigue (n = 14), arthralgia/myalgia (n = 10), neurotoxicity (n = 9) and memory loss (n = 4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies.

From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged &#104 56 years with primary operable breast cancer and &#83 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n=36), fatigue (n=14), arthralgia/myalgia (n=10), neurotoxicity (n=9) and memory loss (n=4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies.

The efficacy of cytotoxic therapy in different anatomical sites can be studied by analyzing the anatomical distribution of recurrences following adjuvant therapy or the rate of response according to site of metastasis. Cumulated data from 7 adjuvant studies showed that the relative reduction in the rate of recurrence was 37% for local and regional recurrences versus 25% for distant metastases. There are only sparse and inconclusive data concerning the anatomical pattern of recurrence according to type of adjuvant chemotherapy. Thus, the majority of trials have not demonstrated significant differences in distribution of metastases in patients receiving different types of adjuvant systemic therapy. The available data on the rate of response in relation to metastatic site showed higher response rates in soft tissue metastases (55%), compared to visceral and bone metastases (40%). Cumulated data from 12 trials showed no differences in response rates between different soft tissue lesions (skin, subcutaneous tissue, lymph nodes, breast), or between metastases demonstrated by paraclinical tests (lung, liver, bone). However, there was a tendency for soft tissue lesions to have a higher response rate (55-60%) than visceral and bone metastases (31-44%). The reason for the observed differences is unknown. At the time of diagnosis soft tissue lesions may be smaller (with better blood supply) than visceral lesions. This might increase the likelihood of response, since experimental data show that the response rate is inversely correlated with tumour burden and tumour size. Another explanation is based on the hypothesis of site-specific clonal selection of tumour cells, which differ with respect to sensitivity to cytotoxic agents. However, the observed differences can also be ascribed to methodological errors or differences in assessing response of tumours at specific sites. Thus, the false positive response rate in soft tissue lesions, evaluated by physical examination, is approximately 20% compared with less than 10% in lung lesions evaluated by x-rays.

Characteristics of primary breast tumours were related to the extent of dissemination, the anatomical location of metastases, and the rate of progression in 863 patients with recurrent breast cancer. The following features were examined: tumour laterality, location within the breast, size, invasion of skin or fascia, presence of residual cancer tissue (RCT) in the mastectomy specimen, and number of positive lymph nodes. Increasing tumour size, increasing number of nodes, and the presence of local invasion and RCT were all associated with a short duration of survival both from initial diagnosis and from first recurrence. None of the factors were related to either the extent of dissemination or the rate of progression. Patients who had their primary tumours located in the medial or central part of the breast had an increased incidence of mediastinal and pleural recurrences respectively. Primary tumours greater than 5 cm, invasion of skin or fascia, and presence of RCT were all associated with an increased incidence of local recurrences. In addition, both RCT and fascial invasion were associated with increased occurrence of brain metastases. Most differences were explainable on the basis of local and regional lymphodynamics. Since the status of the features examined here all vary with time from tumour inception, it is suggested that the impact on prognosis is related to variations in tumour age from inception to primary diagnosis rather than to qualitative biological differences.

The prognosis and pattern of spread were related to body size and menopausal status in 863 patients with recurrent breast cancer. These patients were all enrolled in the adjuvant protocols of the Danish Breast Cancer Cooperative Group. The pattern of spread was illustrated by the number of metastases, the anatomical location of recurrence, and the rate of progression. Body size was estimated as height, weight, Quetelet index (QI), and body surface area (BSA). The body size was unassociated with both recurrence-free interval (RFI) and survival after recurrence (SAR). The groups of patients with different body size had both the same number and the same location of metastases. The tumour growth rates were estimated as clinical rates of progression (i.e. the time elapsed from a single distant metastasis until dissemination). The progression rate was unaffected by body size. Postmenopausal patients had a significantly shorter RFI and SAR compared to premenopausal patients. The number of metastatic sites, the anatomical location of metastases, and the rate of progression were similar in pre- and postmenopausal patients. The study could not confirm most findings from the literature which report a poor prognosis for patients with large body size. Moreover, the results do not suggest interactions between body size, menopausal status, and the clinical course of recurrent breast cancer.

A material of 87 consecutive patients with Ewing's sarcoma referred for treatment in the period 1962-1983 was retrospectively analysed. Thirteen patients had metastases at the time of diagnosis. Of the remainder, 71 received radiation therapy and 32 adjuvant chemotherapy. Survival rate was not influenced by age, sex or treatment delay. Metastatic disease predictably shortened survival (median 6 months vs. 23 months for localized disease). Tumour site did not significantly influence survival rate, although pelvic localization was associated with a slightly shorter median survival. Both pain and objective impairment of movement at presentation correlated to a poorer prognosis, possibly because of larger tumours or soft tissue extension. Adjuvant chemotherapy prolonged recurrence-free survival from a median of 6 months to 16 months, but survival was not improved significantly. Local failure occurred in about 40 per cent, regardless of radiation dose and tumour site. At the time of evaluation, 13 patients (15%) were alive with no evidence of disease and a median follow-up time of 68 months (range 16-196). So far, 2 patients have developed secondary malignancies in irradiated areas (one malignant fibrous histiocytoma and one osteogenic sarcoma).

Of the 3,802 patients enrolled in the DBCG 77 protocols, 863 developed clinical recurrence within a median follow-up time of 4.9 years (range 2.0-7.0). More than 69% of these had their first recurrence confined to a single anatomical site and 12% had more than two metastatic sites. The most common sites were bone (35%), lung (23%), skin (22%), and regional lymph nodes (16%). The observation period after first recurrence was 3.6 years (range 0.8-6.4). Survival after recurrence was significantly related both to the location and the number of metastases. Patients who were given adjuvant chemotherapy (n = 134) had significantly fewer metastatic sites and significantly more frequent liver metastases than untreated patients (n = 50). Patients who received adjuvant tamoxifen (n = 154) had the same number of metastatic sites, but more often had lung metastases than untreated patients (n = 201). These results probably reflect that metastases in different anatomical locations differ with respect to sensitivity to antineoplastic treatments.