E. Van Limbergen

Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer

BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Cosmetic evaluation of breast conserving treatment for mammary cancer. 1. Proposal of a quantitative scoring system

Abstract In a population of 142 patients with stage I and II breast cancer, treated with tumor excision and external radiotherapy, using a wide range of radiation doses and fractionation schedules, an attempt was made to quantify the cosmetic outcome. Quantitative measurements of nipple displacement and breast contour retraction were compared and correlated with qualitative scoring by a panel. In the vast majority, the quantitative assessments correlate very well with subjective, qualitative scoring, making this method relevant for clinical use. There are a few exceptions, mainly cases where localized skin changes such as severe teleangiectasia or skin necrosis affect strongly the cosmetic result but can go undetected in this measuring system. Also limited surgical deformations, which can detract seriously from cosmetic success, particularly when they occur in the medio inferior quadrants, can not always be assessed by this method. The routine use of these measurements in clinical practice is very simple. Only one photograph, taken in standard conditions is needed. Measurements can be carried out quickly, using the plotting device of a treatment planning system. This system may be of great use for follow-up of new treatment modalities and the study of the development of radiation fibrosis in breast cancer.

RADIOTHERAPY BY MULTIPLE FRACTIONS PER DAY (MFD) IN HEAD AND NECK CANCER: ACUTE REACTIONS OF SKIN AND MUCOSA

The feasibility of several unusual fractionation schedules in the radiotherapy of head and neck tumors was assessed, especially the acute reactions of skin and mucosa. All schedules were based on the principle of multiple fractions per day (MFD) leading to highly concentrated treatment series, alternating with rest periods. The fraction sizes used were between 1.6-2 Gy, overall treatment time was about 6 weeks, and total dose ranged from 60 to 67.2 Gy. The most important parameter that was modified was the size of the dose given in one treatment series. The first schedule consisted of two unequal radiation series: 48 Gy/12 days, followed by a second series of 19.2 Gy/4 days after a 3- to 4-week interval. All subsequent treatment schedules were divided in equal series: the first in 2 times 30 Gy, the second in 3 times 22.4 Gy, and the third in 4 times 16 Gy. Comparison of acute reactions in skin and mucosa after these irradiations to different dose levels has made it possible to obtain a precise idea of the time course in the development of radiation induced damage and of the dose-effect relationship. Such dose-response curves will be extremely useful in further studies on the dose-modifying effects of sensitizers and cytostatic drugs. Conclusions of this study: 1. In human oral mucosa, the threshold dose for the development of confluent mucositis (patches of 0.5 cm) after fractionated irradiation appears to be around 20 Gy. 2. Intervals of 12 days allow full repair of mucosa damage after a dose of about 20 Gy and repeating the irradiation leads to an identical reaction after second, third or fourth treatments, demonstrating that no cumulative effect exists for acute damage. This phenomenon could be exploited to reduce the acute side effects in radiotherapy. 3. The reactions observed in skin are less pronounced than those of mucosa, possibly due to the dose distribution of high energy photons. The changes are, however, slower to develop and intervals of 2 weeks are insufficient for the skin to fully recover from the radiation damage. Subsequent treatment series led to a cumulative reaction pattern. 4. Finally, a number of treatments were associated with misonidazole, an anoxic cell sensitizer, which did not appear to modify significantly the radiation reactions in either skin or mucosa.

Local control of operable breast cancer after radiotherapy alone

Abstract 221 patients with operable breast carcinoma stage Tis, T1, T2, T3, N0N1 were treated with radiotherapy alone without tumorectomy. The mean follow-up time was 15.5 years (range 5–22). The annual risk for local recurrence was 3% during the first 5 years and 1% during the following 10 years, resulting in an actuarial local control rate of 75.4% after 15 years. The risk for local recurrence was assessed in multivariate analysis and was significantly related to the size of the tumour measured on mammography ( P = 0.0002), the radiation dose administered ( P = 0.0018), the length of the split-course intervals being longer than 75 days ( P = 0.001) and age ( P = 0.019). Dose was related to response over a wide range as a function of tumour volume. All 18 patients with minimal tumour load (T0 and Pagets disease) treated with doses above 55 Gy in 6 weeks achieved local control. 5-year local control rates ranged from 40 to 100% for T1 carcinomas treated with 45–110 Gy, and from 0 to 95.3% for T2 carcinomas at the same dose. For T3 carcinomas local control varied between 50 and 83% at 60–110 Gy. The risk for local failure increased by 8% per cm tumour diameter. With exclusive radiotherapy, the doses needed to provide local control rates similar to those obtained after tumorectomy and irradiation are 10 Gy higher for T1 (95% 5 year control) and 35 Gy higher for T2 (90% 5 year control).

Stellate ganglion block for the management of hot flashes and sleep disturbances in breast cancer survivors: an uncontrolled experimental study with 24 weeks of follow-up

BACKGROUND We studied the stellate ganglion block (SGB) recently suggested for the treatment of severe vasomotor symptoms and sleep disturbances in breast cancer survivors. Following an initial pilot study, which focused on the acceptability and safety of SGB for this important problem, we evaluated its short- and long-term efficacy. MATERIALS AND METHODS Postmenopausal breast cancer survivors with severe vasomotor symptoms resistant to standard nonhormonal pharmacological intervention were eligible. Diaries were used to measure daily hot flash scores (frequency and intensity) and sleep quality (Pittsburgh Sleep Quality Index) during scheduled visits at baseline, 1, 4, 12 and 24 weeks following the SGB. Efficacy data were analyzed using longitudinal regression models. RESULTS Thirty-four patients participated and none refused the SGB procedure. Most patients received more than one SGB. The pilot study found SGB to be safe. In the main study, hot flash scores were reduced from baseline by 64% [95% confidence interval (CI) -74% to -49%] and 47% (95% CI -62% to -27%) at weeks 1 and 24, respectively. The odds ratio of better sleep quality relative to baseline was 3.4 at week 1 (95% CI 1.6-7.2) and 4.3 at week 24 (95% CI 1.9-9.8). CONCLUSION In the short term, SGB appears to be an effective treatment with acceptable morbidity for some breast cancer survivors with therapy-resistant vasomotor symptoms and/or sleep disturbances. Although sleep quality was maintained out to 24 weeks the efficacy of SGB for hot flashes was reduced over time. A randomized controlled trial is needed to confirm these findings.

Neoadjuvant capecitabine and docetaxel (plus trastuzumab): an effective non-anthracycline-based chemotherapy regimen for patients with locally advanced breast cancer

BACKGROUND To evaluate capecitabine-docetaxel (XT), with trastuzumab (H) in human epidermal growth factor receptor 2 (HER2)-positive disease, in inoperable locally advanced breast cancer (LABC). PATIENTS AND METHODS Patients received up to six neoadjuvant 21-day cycles of capecitabine 900 mg/m(2) twice daily, days 1-14, plus docetaxel 36 mg/m(2), days 1 and 8. Patients with HER2-positive disease also received trastuzumab 6 mg/kg every 3 weeks. The primary end point was pathologic complete response (pCR) rate, evaluated separately in HER2-negative and HER2-positive cohorts. Secondary end points included clinical response rates and tolerability. RESULTS The pCR rate was 15% [95% confidence interval (CI) 7-28] in 53 patients receiving XT and 40% (95% CI 26-55) in 50 patients receiving HXT. After neoadjuvant therapy, 50 patients receiving XT and 45 receiving HXT underwent surgery. No unexpected toxicity was observed: the most common grade ≥3 adverse events were diarrhea/mucositis (30% and 20%, respectively) and grade 3 hand-foot syndrome (11% and 6%, respectively). Disease-free survival and overall survival were similar with XT and HXT after median follow-up of 22 months in the XT cohort and 21 months in the HXT cohort. CONCLUSION Neoadjuvant XT (HXT in HER2-positive disease) is highly effective in inoperable LABC, demonstrating pCR rates of 15% and 40%, respectively. This non-anthracycline-containing regimen offers obvious benefits in early disease, where avoidance of long-term cardiotoxicity is particularly important.

High dose level radiation therapy for local tumour control in esthesioneuroblastoma

Esthesioneuroblastoma is an uncommon tumour of neural crest origin arising in the nasal cavity. This paper is a retrospective review of 7 patients with esthesioneuroblastoma treated at a single institution from May 1974 to July 1990. 5 patients were treated with radiation therapy alone and 2 patients were irradiated after surgical resection. No local or regional occurrence was observed in any patient at 6 months, or at 1, 3, 6, 11.5 and 12 years following treatment. One patient died of intercurrent disease 6 years after radiation therapy. 2 patients died of disease, 1 of distant metastasis at 6 months and the other patient of meningeal carcinomatosis and distant metastases 1 year after treatment. One patient is alive with distant metastases 1 year after treatment. None of the patients experienced significant complications of irradiation. High-dose irradiation (60 Gy or more) alone or in combination with resection is an effective local treatment modality for esthesioneuroblastoma.

Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers

BACKGROUND Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.BACKGROUND Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.

Body mass index and HER-2 overexpression in breast cancer patients over 50 years of age

PurposeIn breast cancer, in vitro as well as in vivo experiments have shown an inverse relationship between HER-2 and steroid hormone receptors. It is unknown whether circulating estrogens affect HER-2 expression. We hypothesize that the postmenopausal body mass index (BMI) as a surrogate marker for bio-available estrogens, is inversely associated with HER-2 over-expression.Patients and methodsA total of 535 women over age 50 or with known postmenopausal status, with a unilateral, not previously treated, operable breast cancer were evaluated the evening prior to surgery for body weight, height, abdominal and hip circumference over a 3 years period. Waist-to-hip ratio (WHR) and BMI were calculated. HER-2, estrogen receptor and progesterone receptor staining was done by immunohistochemistry. All tumours with DAKO 2+ staining were submitted for HER-2 detection by FISH analysis. HER-2 was defined as positive if DAKO 3+ or FISH positive. We assessed the frequency of HER-2 positivity in each of 6 quantiles for all parameters of body composition and tested for a trend in HER-2 expression across the 6 quantiles. Furthermore, we investigated whether BMI contributed, together with other known predictors for HER-2, in a standard multivariate logistic regression model that predicts HER-2 over-expression.ResultsThere is a decrease in HER-2 over-expression per increasing quantile of BMI. In a multivariate model—including both steroid receptors—BMI remains an independent predictor for HER-2 over-expression.ConclusionIn women over age 50 or with known postmenopausal status with an operable breast cancer, there is an inverse association between BMI and HER-2 over-expression.

Radiation-induced sarcoma: analysis of 46 cases.

Abstract A retrospective analysis was performed of 46 cases of sarcoma treated in our institution between 1989 and 2007 that occurred in a previously irradiated area. Eight male and 38 female patients had received radiotherapy, mainly for breast cancer and genitourinary tumours. The interval between irradiation and the diagnosis of sarcoma ranged from 1 to 54 years (median 15 y). The most common clinical findings were a mass, pain and skin dislocation. Angiosarcoma and sarcoma non-otherwise-specified were the most common histological types. Surgical resection was performed in 34 patients (74%) and 5-year survival was 45% when a radical resection was obtained. No 5-year survival was noticed after non-radical resection and in the absence of surgery. Stage and location of the sarcoma were other prognostic factors. Overall 5-year survival was 27% for the whole group.