[Radiation-induced sarcomas after breast cancer: experience of Institute Curie and review of literature]. / Sarcomes radio-induits après cancer du sein: expérience de l'institut Curie et revue de la littérature.

Adjuvant radiotherapy to the breast plays a significant role in preventing local failure in women treated for early stage breast cancer. This fact is supported by multiple clinical trials demonstrating that adjuvant radiotherapy decreases the risk of local recurrence and increases the rate of breast preservation, and actually the rules of adjuvant breast irradiation are clearly established. Sarcomas are a rare but recognized complication of radiation therapy for breast carcinoma, and are associated with poor prognosis. The first case of a bone sarcoma after radiation therapy of breast cancer was described by Beck in 1922. In 1948, Cahan et al. defined the criteria for diagnosis of radiation-induced sarcoma. Since then, some studies have reported the incidence of radiation-induced sarcoma after radiotherapy for different cancers. This article reports and discusses the incidence, management and treatment outcome of radiation-induced sarcomas occurring after radiotherapy for breast cancer in our institute. The incidence, histology, latency of appearance, genesis, their treatment and the prognostic factors of these rare tumors are discussed and the literature is reviewed.

Medullary breast carcinoma: prognostic implications of p53 expression.

Medullary breast carcinoma (MBC) is a rare pathological type of breast cancer. The rate of p53 protein accumulation is higher in MBC than in common invasive ductal carcinoma. Whether this particular feature of MBC influences the outcome after treatment is unknown. We retrospectively analyzed the characteristics, treatment and outcome of 71 patients with MBC treated between 1981 and 1996. The median age was 51 years (range 27-81) and the median clinical tumor size was 25 mm (range 0-70 mm). Breast-conserving treatment was offered when possible: 55 patients had undergone a tumorectomy and radiotherapy while 16 patients had undergone a mastectomy. p53 protein accumulation was determined by immunohistochemistry on paraffin-embedded tumor specimens from 58/71 samples available for this study. The median follow-up for the 56 survivors was 113 months (range 30-241). The 10-year survival and metastasis-free survival rates were 81% and 81.4%, respectively. The local recurrence rate was 16.4%. The two factors predicting outcome were pathological axillary node involvement in the 60 patients who underwent axillary dissection and adjuvant chemotherapy. p53 accumulation was found in 33/58 patients (57%). p53 status was not predictive of survival nor of distant or local recurrences. We confirm that medullary breast carcinoma has a favorable prognosis despite its aggressive pathological features. p53 protein accumulation, found in the majority of MBCs, was not related to outcome.

[Sentinel node and operable breast cancer: utilization of blue dye injection. Pilot study]. / Ganglion sentinelle et cancer opérable du sein: utilisation du bleu patent. Etude pilote.

STUDY AIM: Sentinel node detection in breast cancer can be realized with colorimetric and isotopic procedures often associated. The aim of this study was to report results obtained with blue dye injection only. PATIENTS AND METHOD: From September 1998 to July 1999, blue dye injection was performed in 73 consecutive patients (mean age: 51 years, range: 36-71 years); 51/70 70% were post-menopausal and half of them were under substitute hormonal treatment; 70% of cancers were discovered through routine mammography. There were 12 bilateral cancers, six of them synchronous, and 84% of cancers were located in the external quadrants. Individualization of sentinel node was performed through blue dye injection into the tumor in case of preoperative diagnosis or in the tumoral site in case of discovery of the cancer through extemporaneous histological examination. RESULTS: 71 out of 73 cancers were classified pT1 and 70% measured 10 mm and over. Individualization of sentinel node failed in two obese patients. Sentinel node invasion concerned one node (n = 7), two nodes (n = 1) and three nodes (n = 1). Conservative treatment was performed in 72 patients out of 73; in case of sentinel node invasion, axillary irradiation was performed without reoperation. CONCLUSION: Blue dye injection for sentinel node individualization is an accurate technique in selected patients in case of small tumors. Reoperation can be avoided and replaced by axillary irradiation in case of N+ tumors. Duration of hospitalization was 48 hours or under in 70/73 patients. Nevertheless isotopic procedure must be recommended as a routine technique in learning centers and for most surgical teams.

[Radiotherapy of cancer of the breast. Technical problems and new approaches]. / Radiothérapie du cancer du sein. Problèmes techniques et nouvelles approches.

Technical problems often arise during irradiation to the breast, chest wall, and regional lymph nodes. The following are among the most frequently encountered problems: avoidance of normal tissues (heart and lungs) during chest wall, internal mammary nodes, and large breast irradiations; dose heterogeneity in large breasts; under- or overdosage at field junctions (breast medial tangent and internal mammary fields in particular). Various technical solutions have been offered: modified treatment positions, field inclinations, and conformal irradiation. Many are currently under evaluation. These new technical approaches in breast cancer irradiation require modern facilities for imaging, simulation, and dosimetry, which help to individually design treatment planning.

[Breast cancers with central localization: conservative treatment by tumorectomy with ablation of the areolar plaque]. / Cancers du sein à localisation centrale: traitement conservateur par tumorectomie avec ablation de la plaque aréolo-mamelonnaire.

OBJECTIVES: In breast cancer, retroareolar tumors are observed in 5 to 20% of cases; mammectomy is the conventional treatment. Conservative surgery was used in this series of 36 patients with retroareolar cancer situated less than 2 cm from the areola. PATIENTS AND METHODS: Tumorectomy with resection of the areolar plaque was followed by radiotherapy. Six patients had Paget's disease of the nipple, 64% were in classes T0 or T1 and 36% in T2. Chemotherapy or radiotherapy was given for tumor reduction prior to surgery in 8 patients. Wide tumorectomy with resection of the areolar plaque and gland remodeling was performed in all patients. Three plastic surgery techniques were used. Mean tumor size was 17.3 mm (8 to 33 mm). The areola was invaded in 16 patients (44%) and the derma or retroareolar ducts in 26 (72%). RESULTS: The mean distance between the tumor and skin surface was 3.8 mm. The section surface was in healthy tissue in 31 patients and 2 patients underwent subsequent surgery for mammectomy. All patients had either pre-operative (n = 4) or post-operative (n = 32) radio-therapy. Secondary reconstruction of the nipple was performed in 14 patients. CONCLUSION: Histology findings and esthetic results suggested that this conservative approach can be proposed when the tumor is located close to the areola, as confirmed by our series and results from other teams using the same technique.

External radiotherapy for carcinoma of the eyelid: report of 850 cases treated.

PURPOSE: We report a retrospective series of 850 patients treated by external irradiation for carcinoma of the eyelid at Institut Curie and we compare our results with other techniques: brachytherapy and surgery. METHODS AND MATERIALS: Eight hundred fifty patients were treated by external radiotherapy for carcinoma of the eyelid. None of these patients have been previously treated. All the patients were classified according to the TNM classification of (UICC). We distinguished five histological types and five clinical groups according to the site of the skin tumor. Three modalities of external radiotherapy were used: contact therapy, conventional radiotherapy, and electrontherapy. We reviewed the clinical files of the 850 patients who went regularly at follow-up visits. RESULTS: We report the 5-year survival results--alive with no evidence of disease: 72%; alive with progression: 2%; died from tumor progression: 0.5%; died from intercurrent disease: 19.5%; and lost to follow-up: 5%. The 5-year local control rate was 97.5%. We observed 45 failures--lymph node, metastatic, and local--and emphasize this last group by presenting the results of treatment of these local failures. We studied the complications of treatment: 2.3% of corneal complications, 2% of cataracts, and 1.4% of serious ocular complications. CONCLUSIONS: Our results concerning local failures and loss of the eye are comparable to those reported for other techniques involving brachytherapy or surgery. Overall, external radiotherapy is a safe and effective treatment, as it ensures a high local control rate and provides perfectly satisfactory functional and esthetic results. It seemed particularly useful to report this series in that few publications are available on this subject that, nevertheless, constitutes a topical issue.

[Breast cancer after preventive subcutaneous mastectomy]. / Cancer du sein après mammectomie sous-cutanée préventive.

Because of a family history of breast cancer, a 51-year-old patient underwent bilateral subcutaneous mammectomy in 1988. In February 1994 she presented with a nodule in the supramedial quadrant on the left. Needle biopsy suggested galactophoric adenocarcinoma which was confirmed histologically. A 1.5 cm tumour was removed together with a 3 cm reliquat of glandular tissue. Twelve axillary nodes were dissected and were found to be free of neoplastic infiltration. Hormone receptors were positive. Post-operative radiotherapy was performed. The outcome is unchanged at 6 months. Bilateral subcutaneous mammectomy can be proposed as a preventive measure in patients at risk, but as demonstrated by this case, exeresis is usually incomplete. The level of protection actually achieved is thus questionable. Clinicians should be aware of the risk of breast cancer developing after such elective operations since early screening programmes and the development of genetic methods based on the search for BRCA1 and BRCA2 genes will undoubtedly increase the number of patients requesting preventive measures.

Breast cancer in elderly women: a retrospective analysis of combined treatment with tamoxifen and once-weekly irradiation.

PURPOSE: To evaluate retrospectively the efficacy of combined modality treatment (hormone therapy and hypofractionated radiotherapy) in a population of very elderly women with breast cancer. METHODS AND MATERIALS: Records on 70 patients of median age 81 years, treated between January 1988 and February 1994, whose median follow-up is now 36 months, have been evaluated. Information obtained included clinical stage at diagnosis, histology, tumor grading, hormone receptor levels, details of treatment, type of failure, survival data, and status at last follow-up examination. Treatment consisted of Tamoxifen 20 mg daily and a hypofractionated course of high dose-per-fraction once-weekly radiotherapy. In the majority of cases this consisted of seven exposures of 6.5 Gy (five to the involved breast, and two to the tumor bed) given over 6 weeks, on a 60Co unit. Nodes were treated when clinically involved, to a dose of 27.5-30 Gy in five to six fractions. RESULTS: At median follow-up of 36 months, the overall survival rate is 87% [confidence interval (CI) 78-95%], the disease specific survival rate is 88% (CI 80-96%), and 72% (CI 60-84%) of patients are free of disease. The local control rate at 36 months is 86% (CI 76-95%). When analyzed by T stage, 81% of T1 patients, 96% of T2 patients, 60% of T3 patients and, paradoxically 100% of T4 patients were in local control at 36 months, although at that point there were just four such patients available for consideration in the T4 group. Initial response to hormone therapy does not appear to be a predictive indicator for ultimate loco-regional control. There is a trend towards greater probability of loco-regional failure if total dose delivered to the breast is less than 35 Gy. CONCLUSIONS: Women of elderly age are often denied combined modality therapy, because of coexistant disease or fears held by the responsible physicians that elderly patients are unable to tolerate surgery or protracted courses of radiotherapy. Consequently, many are treated by tamoxifen alone with poor results. This study demonstrates that very high rates of loco-regional control are achievable using hormonal treatment combined with high dose-per-fraction once-weekly radiotherapy.

Iridium-192 versus cobalt-60 boost in 3-7 cm breast cancer treated by irradiation alone: final results of a randomized trial.

This prospective randomized trial compared an iridium-192 implant boost with a cobalt-60 external irradiation boost to the primary tumor site, in 255 patients with breast cancers 3-7 cm in diameter. All patients had a partial (> 50%) or complete response following primary external beam irradiation of 58 Gy to the whole breast, as well as irradiation to the axillary, supraclavicular and internal mammary nodes. Patients with clinically positive axillary nodes also received a cobalt-60 10-15 Gy boost to the inferior axilla. All patients had core biopsy only. Both groups were comparable in age, tumor size, node involvement, grade, and progesterone receptor levels. The boost dose was 20 Gy in both groups. At the median 8-year follow-up, the breast recurrence risk was 24% in the iridium group and 39% in the cobalt group (p = 0.02). When adjusted to other prognostic and treatment factors, the brachytherapy boost decreased the breast recurrence risk by 60%. The 8-year breast preservation rates were 81% and 67%, respectively (p = 0.024). Cosmetic outcome in both groups was evaluated in 120 patients with a minimum 3-year follow-up and was comparable in both groups. This study demonstrates that in selected patients with large tumors treated with irradiation alone, local control and breast preservation rates are improved by the use of brachytherapy to boost the primary tumor.

Simultaneous bilateral breast carcinomas: a retrospective review of 149 cases.

PURPOSE: To evaluate clinical and biological characteristics as well as treatment outcome in simultaneous bilateral breast carcinomas. METHODS AND MATERIALS: Between 1981 and 1990, 149 patients were diagnosed to have simultaneous bilateral breast carcinoma, defined as tumor arising in both breasts within a maximum of a 6-month interval, in the absence of distant metastases. The median age was 58. Out of a total of 298 tumors, the clinical tumor size was T0-T1 in 40%, T2 in 45%, and T3-T4 in 15% of tumors. The majority of patients (83%) were clinically node negative. Seventy-eight percent of all tumors were classified ductal invasive; 6% were invasive lobular carcinomas; in situ tumors were present in 9%. More than two-thirds of all tumors were well or moderately well differentiated. Tumors were estrogen positive in 86% and progesterone positive in 69% of 62% of patients for whom this information was available in both tumors. Treatment had been by bilateral mastectomy in 43%, by exclusive irradiation in 16%, and by combined surgery and radiation in 41%. RESULTS: Median follow-up was 68 months (11-141). A number of positive correlations existed between the tumors in both breasts more often than by chance alone: These were the presence of lobular carcinomas in both breasts (p = 0.06), the same histological grade (p = 0.002), similar ER (p = 0.03) and PR (p = 0.01) status. Five-year rates for survival and disease-free interval were 86% (80-92) and 70% (62-78), respectively. For each patient the stage of the largest tumor at diagnosis was defined as maximum stage. When survival figures were compared between each maximum stage and matched stages of a group of unilateral breast cancer patients treated during the same time interval in our institute, bilateral breast cancer fared not worse than unilateral breast tumors. Treatment related complications occurred in eight patients (5%). CONCLUSION: Simultaneous bilateral breast carcinomas have similar biological, but not clinical, features more frequently than would be predicted by chance alone. So far, the number of patients is too small, and the follow-up is too short to determine whether or not the prognosis is equivalent to that of unilateral breast cancer patients of equal stage. Bilateral conservative treatment is feasible with acceptable cosmetic results and toxicity by using carefully designed radiotherapy techniques.

[Superoxide dismutase (Cu/Zn) in cutaneous application in the treatment of radiation-induced fibrosis]. / Superoxyde dismutase (Cu/Zn) en application cutanée dans le traitement des fibroses radio-induites.

The aim of the paper consists to select criterias of the therapeutic effect of superoxide-dismutase (PEG-SOD) administrated as an ointment twice a day for 3 months. An original scoring method including qualitative and quantitative data was set up in order to appreciate the importance of the fibrosis and its variations when under local administration of PEG-SOD. Clinical and paraclinical controls were made as T0, T1 (6 weeks), T2 (3 months), T3 (6 months). After 6 months, results enabled us to show PEG-SOD in its galenic form was efficient on radiofibrosis with a 41% score reduction compared to pretreatment score T0, thus an improvement of nearly half of the potential theoretical recovery. The therapeutic efficiency was greater on the most recent fibrosis and there was a chronological order to the different recovery stages. After 6 weeks of administration pains were reduced or stopped; then after 3 months of treatment fibrous texture broke up and softened. An effective reduction of the surface as well as lightened of the pigmentation would not usually start until the 4th month after the start of treatment. PEG-SOD is thus an enzyme the therapeutic interest of which offers interesting prospects. The score which was set up enable a fair evaluation of the intensity and the variations of the treated fibrosis. A prospective study is currently on going in order to research the biological conditions in which the enzyme reacts.

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6.

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (> 50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Age as prognostic factor in premenopausal breast carcinoma.

Whether or not young age at diagnosis is an adverse prognostic factor in breast cancer has long been controversial, in part because much previous work has not taken due account of menopausal status and confounding factors. We have analysed the influence of age on prognosis in a consecutive series of 1703 patients with stage I-III breast cancer. All were premenopausal and all were treated in one centre (Institut Curie, Paris) between 1981 and 1985. Mean age was 44 years (range 23-55) and median follow-up was 82 months. Younger patients had significantly lower survival rates and higher local and distant relapse rates than older patients. The hazard rate of relapse decreased over time in the youngest age group (< or = 33) to reach that of older patients after 5 years. The relation between the hazard of recurrence and age was a continuous one, best fitted by a log-linear function and indicating a 4% decrease in recurrence for every year of age. Multivariate analysis of both survival and disease-free interval demonstrated that the worse prognosis of young age was independent of other factors such as clinical tumour size, clinical node status, histological grade, hormone receptor status, locoregional treatment procedure, and adjuvant systemic therapy. This difference in outlook has yet to be explained biologically but it does suggest the need for a closer look at the natural history of breast cancer in young women.

Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. The Breast Carcinoma Collaborative Group of the Institut Curie.

Axillary dissection in early breast cancer remains controversial because of its substantial side-effects and because its value with respect to recurrence or survival has not been unequivocally proven. Between 1982 and 1987, 658 patients were included in a prospective randomised comparison of lumpectomy alone with lumpectomy plus axillary dissection. All patients had a unilateral breast tumour not exceeding 3 cm in diameter and lymph-node involvement or metastases. Radiation therapy was given to both groups. The two groups of patients were similar with respect to mean age, TNM stage, and presence of hormonal receptors. Median follow-up was 54 months. 5-year survival of the patients was 94.2% (95% Cl: 92.1-96.4). There was a significant advantage in survival in the axillary dissection group (p = 0.014). Recurrence of tumour in the breast was similar in the two groups but visceral metastases, supraclavicular metastases, and lymph-node recurrences were less frequent in the axillary dissection group. Survival was related to the age of the patients (p = 0.005), the presence of positive nodes (p = 0.006), the histological grading (p less than 0.0001), and the presence of hormonal receptors (progesterone p = 0.0008, oestrogen p less than 0.0001). Treatment-adjusted relative risk was 2.4 (95% Cl: 1.3-4.2). The findings show that axillary dissection is justified for treatment of small breast cancers, although whether the better survival is due to axillary clearance itself or to adjuvant treatment for lymph-node involvement is unclear.

[Primary epidermoid carcinoma of the breast. Clinical, histopathologic and prognostic study of 14 patients]. / Carcinome épidermoïde primitif du sein. Etude clinique, histopathologique et pronostique de 14 patientes.

We reviewed the charts of 14 patients with epidermoid breast carcinoma, whether pure or associated with a minor glandular component. These patients were treated between 1970 and 1989 at the Institut Curie and represented 0.06% of all breast cancer patients treated during the same period. No clinical or radiological criteria could help to discriminate these forms from other types of breast cancer. Four out of 13 patients with initial axillary node dissection had nodal involvement. Various combinations of surgery and radiotherapy were used to treat these patients. One out of 14 hormone receptor levels was positive. Median survival was 54 months (9 months-144 months). Two patients had a local recurrence and 7 had metastasis. No event occurred beyond 5 years of follow-up. This suggest that the outcome of epidermoid breast tumors is closer to that of other epidermoid tumors, rather than to other types of breast cancer.

Breast irradiation in the lateral decubitus position: technique of the Institut Curie.

Breast irradiation in the lateral decubitus (LD) position is a technique used at the Institut Curie for more than 30 years in the breast-conserving management of patient with breast cancer. This technique is described in detail in this article. The patient's position allows the breast to flatten over a support, hence providing a rather homogeneous thickness throughout the treated volume. Dose at mid-thickness on the beam axis can be easily determined from entrance and exit dose measurements. Disadvantages and advantages of the LD technique are discussed. We presently recommend this technique for patients with large breasts (more than 6 cm thickness in LD position).

[Concomitant association of radiotherapy and chemotherapy in inflammatory breast cancer. Initial results of phase II trial]. / Association concomitante radiothérapie-chimiothérapie dans le cancer du sein inflammatoire. Résultats préliminaires d'un essai phase II.

Between 01/1986 and 12/1987, 15 patients displaying inflammatory breast carcinoma, were included in a phase II trial. The aim of the treatment was to increase the local response by the potentiation of radiotherapy by concomitant chemotherapy (continuous infusion 5 FU, vindésine, Cyclophosphamide). This treatment consisted of four series of radiotherapy: 18 Gy/10 fractions/12 days spaced by a 2-week rest period between series, to a total dose of 72 GY to the breast tumor. Chemotherapy was undertaken over the first 5 days of radiotherapy in each series. Two patients had metastatic disease (bone-liver). Seven patients had not responded to an initial standard chemotherapy treatment. Six patients were initially treated with the concomitant association. The treatment was very well tolerated by all 15 patients. Inflammation disappeared in all patients within 6 weeks after the beginning of the association. A tumor decrease was observed in all patients, complete in 60%. All 7 patients who had failed initial chemotherapy recurred 8 to 19 months after the association, despite a good response; 3 died of disease and 4 were in local or metastatic evolution on last follow up. The 6 patients treated initially with the association Radiotherapy/Chemotherapy were all alive with a 27 months median follow up (24-40). 2/6 mastectomies were performed: one for breast recurrence and one for persistent residual mass. In this latter patient histologic examination showed no residual active tumor. 4/6 patients have their breast preserved without sequelae. High local response rates were observed with the concomitant combination of radiotherapy and chemotherapy, specially when administered as initial treatment.

Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patients. III: Measurement of mutant frequency to 6-thioguanine resistance.

The mutant frequencies (MF) at the HPRT locus of peripheral blood lymphocytes collected from breast cancer patients before and after treatment according to a defined protocol of the Institut Curie were compared to those from healthy donors. The treatment involved either a local radiotherapy (RT1) followed by a chemotherapy (CT2) or a chemotherapy (CT1) followed by a radiotherapy (RT2). In accord with others, we observed no significant difference in the MF to 6-thioguanine resistance (6TG) in T lymphocytes in the control and breast cancer groups before treatment. When the effect of CT or RT either alone or in combination was analysed, the increase observed in MF can be wholly accounted for by the effect of radiation. In this study, the effect of chemotherapy on mutation did not achieve significance. Circulating T lymphocytes are mainly in the G0 phase of the cell cycle and thus would not be mutated by drugs which preferentially affect dividing cells, whereas such cells could still mutate when submitted to ionizing radiation.