Benefit of respiratory gating in the Danish Breast Cancer Group partial breast irradiation trial.

BACKGROUND AND PURPOSE: Partial breast irradiation (PBI)has beenthe Danish Breast Cancer Group(DBCG) standard for selected breast cancer patients since 2016 based onearlyresults from the DBCG PBI trial.During trial accrual, respiratory-gated radiotherapy was introduced in Denmark. This study aims to investigate the effect of respiratory-gating on mean heart dose (MHD). PATIENTS AND METHODS: From 2009 to 2016 the DBCG PBI trial included 230 patientswith left-sided breast cancer receiving external beam PBI, 40 Gy/15 fractions/3 weeks.Localization of the tumor bed on the planning CT scan, the use of respiratory-gating, coverage of the clinical target volume (CTV), and doses to organs at risk were collected. RESULTS: Respiratory-gating was used in 123 patients (53 %). In 176 patients (77 %) the tumor bed was in the upper and in 54 patients (23 %) in the lower breast quadrants. The median MHD was 0.37 Gy (interquartile range 0.26-0.57 Gy), 0.33 Gy (0.23-0.49 Gy) for respiratory-gating, and 0.49 Gy (0.31-0.70 Gy) for free breathing, p < 0.0001. MHD was < 1 Gy in 206 patients (90 %) and < 2 Gy in 221 patients (96 %). Respiratory-gating led to significantly lower MHD for upper-located, but not for lower-located tumor beds, however, all MHD were low irrespective of respiratory-gating. Respiratory-gating did not improve CTV coverage or lower lung doses. CONCLUSIONS: PBI ensured a low MHD for most patients. Adding respiratory-gating further reduced MHD for upper-located but not for lower-located tumor beds but did not influence target coverage or lung doses. Respiratory-gating is no longer DBCG standard for left-sided PBI.

Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The Danish Breast Cancer Group Partial Breast Irradiation Trial.

PURPOSE: On the basis of low risk of local recurrence in elderly patients with breast cancer after conservative surgery followed by whole breast irradiation (WBI), the Danish Breast Cancer Group initiated the noninferiority external-beam partial breast irradiation (PBI) trial (ClinicalTrials.gov identifier: NCT00892814). We hypothesized that PBI was noninferior to WBI regarding breast induration. METHODS: Patients operated with breast conservation for relatively low-risk breast cancer were randomly assigned to WBI versus PBI, and all had 40 Gy/15 fractions. The primary end point was 3-year grade 2-3 breast induration. RESULTS: In total, 865 evaluable patients (434 WBI and 431 PBI) were enrolled between 2009 and 2016. Median follow-up was 5.0 years (morbidity) and 7.6 years (locoregional recurrence). The 3-year rate of induration was 9.7% for WBI and 5.1% for PBI (P = .014). Large breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large-breasted patients versus 6% (WBI) and 5% (PBI) for small-breasted patients. PBI showed no increased risk of dyspigmentation, telangiectasia, edema, or pain, and patient satisfaction was high. Letrozole and smoking did not increase the risk of radiation-associated morbidity. Sixteen patients had a locoregional recurrence (six WBI and 10 PBI; P = .28), 20 patients had a contralateral breast cancer, and eight patients had distant failure (five WBI and three PBI). A nonbreast second cancer was detected in 73 patients (8.4%), and there was no difference between groups. CONCLUSION: External-beam PBI for patients with low-risk breast cancer was noninferior to WBI in terms of breast induration. Large breast size was a risk factor for radiation-associated induration. Few recurrences were detected and unrelated to PBI.

Internal Mammary Node Irradiation in Patients With Node-Positive Early Breast Cancer: Fifteen-Year Results From the Danish Breast Cancer Group Internal Mammary Node Study.

PURPOSE: The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort. PATIENTS AND METHODS: This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat. RESULTS: During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups. CONCLUSION: In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

Hypofractionated Versus Standard Fractionated Radiotherapy in Patients With Early Breast Cancer or Ductal Carcinoma In Situ in a Randomized Phase III Trial: The DBCG HYPO Trial.

PURPOSE: Given the poor results using hypofractionated radiotherapy for early breast cancer, a dose of 50 Gy in 25 fractions (fr) has been the standard regimen used by the Danish Breast Cancer Group (DBCG) since 1982. Results from more recent trials have stimulated a renewed interest in hypofractionation, and the noninferiority DBCG HYPO trial (ClincalTrials.gov identifier: NCT00909818) was designed to determine whether a dose of 40 Gy in 15 fr does not increase the occurrence of breast induration at 3 years compared with a dose of 50 Gy in 25 fr. PATIENTS AND METHODS: One thousand eight hundred eighty-two patients > 40 years of age who underwent breast-conserving surgery for node-negative breast cancer or ductal carcinoma in situ (DCIS) were randomly assigned to radiotherapy at a dose of either 50 Gy in 25 fr or 40 Gy in 15 fr. The primary end point was 3-year grade 2-3 breast induration assuming noninferiority regarding locoregional recurrence. RESULTS: A total of 1,854 consenting patients (50 Gy, n = 937; 40 Gy, n = 917) were enrolled from 2009-2014 from eight centers. There were 1,608 patients with adenocarcinoma and 246 patients with DCIS. The 3-year rates of induration were 11.8% (95% CI, 9.7% to 14.1%) in the 50-Gy group and 9.0% (95% CI, 7.2% to 11.1%) in the 40-Gy group (risk difference, -2.7%; 95% CI, -5.6% to 0.2%; P = .07). Systemic therapies and radiotherapy boost did not increase the risk of induration. Telangiectasia, dyspigmentation, scar appearance, edema, and pain were detected at low rates, and cosmetic outcome and patient satisfaction with breast appearance were high with either no difference or better outcome in the 40-Gy cohort compared with the 50-Gy cohort. The 9-year risk of locoregional recurrence was 3.3% (95% CI, 2.0% to 5.0%) in the 50-Gy group and 3.0% (95% CI, 1.9% to 4.5%) in the 40-Gy group (risk difference, -0.3%; 95% CI, -2.3% to 1.7%). The 9-year overall survival was 93.4% (95% CI, 91.1% to 95.1%) in the 50-Gy group and 93.4% (95% CI, 91.0% to 95.2%) in the 40-Gy group. The occurrence of radiation-associated cardiac and lung disease was rare and not influenced by the fractionation regimen. CONCLUSION: Moderately hypofractionated breast irradiation of node-negative breast cancer or DCIS did not result in more breast induration compared with standard fractionated therapy. Other normal tissue effects were minimal, with similar or less frequent rates in the 40-Gy group. The 9-year locoregional recurrence risk was low.

Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1.

Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.

The NAME trial: a direct comparison of classical oral Navelbine versus Metronomic Navelbine in metastatic breast cancer.

Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.

[Prevention of skeletal related events in patients with bone metastases from solid tumours]. / Forebyggelse af skeletrelaterede hændelser hos patienter med knoglemetastaser ved solide tumorer.

This article is based on a systematic literature search and meta-analyses of clinical data regarding effects of bisphosphonates (BP) and denosumab (DS) on preventing skeletal related events (SRE) in patients with bone metastases from solid tumours. Although there are pharmacological differences between the different types of BP no major differences were observed between BP in preventing SRE or in adverse events. Treatment with DS has in three randomised trials showed a greater effect than BP in preventing SRE. The optimal choice of bone-anti-resorptive agent should depend on the patient's general condition, renal function and treatment logistics.

Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group.

UNLABELLED: During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required. MATERIAL AND METHODS: A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus. RESULTS: The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes. CONCLUSION: The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group.

PURPOSE: The objective of this phase III study was to compare the efficacy of gemcitabine plus docetaxel (GD) versus docetaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Predominantly human epidermal growth factor receptor 2 (HER2) -negative patients were randomly assigned to gemcitabine (1,000 mg/m(2)) on days 1 and 8 plus docetaxel (75 mg/m(2)) on day 8 or to docetaxel (100 mg/m(2)) on day 1, every 21 days. Patients were untreated or had prior (neo)adjuvant chemotherapy or a single anthracycline-based chemotherapy regimen for metastatic breast cancer. The primary end point was time to progression (TTP), and secondary end points were overall survival (OS), response rate (RR), and toxicity. RESULTS: A total of 170 patients were allocated to GD, and 167 were allocated to docetaxel. Median TTP on GD was 10.3 months versus 8.3 months on docetaxel (hazard ratio [HR], 0.77; 95% CI, 0.59 to 1.01; log-rank P = .06). The adjusted Cox proportional model for TTP showed a significant difference favoring the combination (HR, 0.68; 95% CI, 0.51 to 0.90; P = .007). However, RR was similar (GD, 36%; docetaxel, 34%), and OS was not different (P = .57). Grades 3 to 4 neutropenia was common (GD, 75%; docetaxel, 69%); infection was reported in 26% and 21% of patients in the GD and docetaxel groups, respectively. Grades 3 to 4 thrombocytopenia was more frequent with GD (GD, 16%; docetaxel, 0.6%), and peripheral neuropathy was higher with docetaxel (GD, 5%; docetaxel, 16%). CONCLUSION: GD compared with docetaxel demonstrated increased TTP in metastatic breast cancer. However, RR and OS were similar. Thus, the addition of gemcitabine failed to demonstrate any clinically meaningful benefit when combined with docetaxel.

Effect of obesity on prognosis after early-stage breast cancer.

PURPOSE: This study was performed to characterize the impact of obesity on the risk of breast cancer recurrence and death as a result of breast cancer or other causes in relation to adjuvant treatment. PATIENTS AND METHODS: Information on body mass index (BMI) at diagnosis was available for 18,967 (35%) of 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006 with complete follow-up for first events (locoregional recurrences and distant metastases) up to 10 years and for death up to 30 years. Information was available on prognostic factors and adjuvant treatment for all patients. Univariate analyses were used to compare the associations of known prognostic factors and risks of recurrence or death according to BMI categories. Cox proportional hazards regression models were used to assess the influence of BMI after adjusting for other factors. RESULTS: Patients with a BMI of 30 kg/m(2) or more were older and had more advanced disease at diagnosis compared with patients with a BMI below 25 kg/m(2) (P < .001). When data were adjusted for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased by 46%, and the risk of dying as a result of breast cancer after 30 years was significantly increased by 38% for patients with a BMI of 30 kg/m(2) or more. BMI had no influence on the risk of locoregional recurrences. Both chemotherapy and endocrine therapy seemed to be less effective after 10 or more years for patients with BMIs greater than 30 kg/m(2). CONCLUSION: Obesity is an independent prognostic factor for developing distant metastases and for death as a result of breast cancer; the effects of adjuvant therapy seem to be lost more rapidly in patients with breast cancer and obesity.

[Severe hypercortisolaemia associated with progression of small cell lung cancer]. / Svaer hyperkortisolaemi ved progression af småcellet lungecancer.

Small cell lung cancer accounts for about 15% of all cases of lung cancer and is a highly chemo-sensitive disease, but with a high rate of relapse following induction chemotherapy. Small cell lung cancer is often associated with various paraneoplastic syndromes, and we present a case where progression was dominated by a severe endocrine disorder, and present how treatment with the correct chemotherapy improved the patients clinical and biochemical condition.

Post-mastectomy radiotherapy in Denmark: from 2D to 3D treatment planning guidelines of The Danish Breast Cancer Cooperative Group.

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.

[Radiation myelopathy. Four case reports]. / Strålemyelopati. En beskrivelse af fire tilfaelde.

Chronically progressive (permanent) radiation myelopathy is a serious complication to irradiation of head/neck carcinoma. We describe four patients who developed stationary neurological deficits with a considerable reduction in function. One patient received a radiation dose below 50 Gy and the others up to 58 Gy against the cervical medulla. One patient developed an intramedullary syrinx.