Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location

In breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998–2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63–1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02–1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54–1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.     

Predictive impact of urokinase-type plasminogen activator: plasminogen activator inhibitor type-1 complex on the efficacy of adjuvant systemic therapy in primary breast cancer

One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system. This system comprises of, among others, the urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1). In this study we investigated whether the uPA:PAI-1 complex is associated with the responsiveness of patients with primary breast cancer to adjuvant systemic therapy. Quantitative enzyme-linked immunosorbent assays were used to assess the levels of uPA, PAI-1, and uPA:PAI-1 complex in 1119 tumors of patients with primary invasive breast cancer. These patients were followed for a median follow-up time of 59 months (range, 2-267 months) after the primary diagnosis. Correlations with well-known clinicopathological factors, and univariate and multivariate survival analyses were performed. High uPA:PAI-1 complex levels were correlated with an adverse histological grade, and inversely associated with negative estrogen and progesterone receptor status. High tumor levels of uPA:PAI-1 complex predicted an early relapse in the univariate relapse-free survival analysis (P < 0.001). The multivariate analysis showed that high uPA:PAI-1 complex levels were associated with a decreased relapse-free survival time (P = 0.033), independently of age, tumor size, number of lymph nodes affected, progesterone receptor status, uPA, adjuvant endocrine, and chemotherapy. More important, it was demonstrated that there is a larger benefit from adjuvant chemotherapy for patients with higher versus lower tumor levels of uPA:PAI-1 complex. The results of this study imply that the expression of uPA:PAI-1 complex independently predicts the efficacy of adjuvant chemotherapy in patients with primary breast cancer.     

Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study.

PURPOSE: Febrile neutropenia (FN) is a major complication of chemotherapy. Antibiotics as well as granulocyte colony-stimulating factor (G-CSF) are effective in preventing FN. This multicenter randomized phase III trial determines whether the addition of G-CSF to antibiotic prophylaxis can further reduce the incidence of FN in patients with small-cell lung cancer (SCLC) at the risk of FN. PATIENTS AND METHODS: Patients (N = 175) were stratified for stage of disease, performance status, age, and prior chemotherapy treatment, and were randomly assigned for treatment with cyclophosphamide, doxorubicin, and etoposide (CDE), followed by prophylactic antibiotics alone (ciprofloxacin and roxithromycin) or by antibiotics in combination with G-CSF on days 4 to 13. RESULTS: In cycle 1, 20 patients (24%) in the antibiotics group developed FN compared with nine patients (10%) in the antibiotics plus G-CSF group (P = .01). In cycles 2 to 5, the incidences of FN were practically the same in both groups (17% v 11%). Only the treatment parameters (odds ratio, 0.33; 95% CI, 0.14 to 0.78) and age (1.067 per year; 95% CI, 1.013 to 1.0124) were related to the probability of FN in cycle 1. CONCLUSION: Primary G-CSF prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in SCLC patients at the risk of FN with the first cycle of CDE chemotherapy. For patients with similar risk of FN, the combined use of prophylactic antibiotics plus G-CSF can be considered, specifically in the first cycle of chemotherapy.     

Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923).

BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.     

Continuity of care for patients with de novo metastatic cancer during the COVID-19 pandemic: A population-based observational study

During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1–12 2020: pre-COVID-19, weeks 12–20 2020: 1st peak, weeks 21–41 2020: recovery, weeks 42–53 2020: 2nd peak, weeks 1–20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77–0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72–0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p < .001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.     

Pattern of follow-up care and early relapse detection in breast cancer patients

Routine breast cancer follow-up aims at detecting second primary breast cancers and loco regional recurrences preclinically. We studied breast cancer follow-up practice and mode of relapse detection during the first 5 years of follow-up to determine the efficiency of the follow-up schedule. The Netherlands Cancer Registry provided data of 6,509 women, operated for invasive non-metastatic breast cancer in 2003–2004. In a random sample including 144 patients, adherence to follow-up guideline recommendations was studied. Mode of relapse detection was studied in 124 patients with a second primary breast cancer and 160 patients with a loco regional recurrence. On average 13 visits were performed during the first 5 years of the follow-up, whereas nine were recommended. With one, two and three medical disciplines involved, the number of visits was 9, 14 and 18, respectively. Seventy-five percent (93/124) of patients with a second primary breast cancer, 42 % (31/74) of patients with a loco regional recurrence after breast conserving surgery and 28 % (24/86) of patients with a loco regional recurrence after mastectomy had no symptoms at detection. To detect one loco regional recurrence or second primary breast cancer preclinically, 1,349 physical examinations versus 262 mammography and/or MRI tests were performed. Follow-up provided by only one discipline may decrease the number of unnecessary follow-up visits. Breast imaging plays a major and physical examination a minor role in the early detection of second primary breast cancers and loco regional recurrences. The yield of physical examination to detect relapses early is low and should therefore be minimised.