The dynamic reproduction index: accurate determination from incidence and application for an early warning system

Two methods of calculating the reproduction index from daily new infection data are considered, one by using the generation time tG as a shift (RG), and an incidence-based method directly derived from the differential equation system of an SIR epidemic dynamics model (RI). While the former is shown to have few in common with the true reproduction index, we find that the latter provides a sensitive detection device for intervention effects and other events affecting the epidemic, making it well-suited for diagnostic purposes in policy making. Furthermore, we introduce a similar quantity, [Formula], which can be calculated directly from RG. It shows largely the same behaviour as RI, with less fine structure. However, it is accurate in particular in the vicinity of R = 1, where accuracy is important for the corrrect prediction of epidemic dynamics. We introduce an entirely new, self-consistent method to derive, from both quantities, an improved [Formula] which is both accurate and contains the details of the epidemic spreading dynamics. Hence we obtain R accurately from data on daily new infections (incidence) alone. Moreover, by using RI instead of RG in plots of R versus incidence, orbital trajectories of epidemic waves become visible in a particularly insightful way, demonstrating that the widespread use of only incidence as a diagniostic tool is clearly inappropriate. PACS numbers:

A new Reproduction Index Ri and its Usefulness for Germany's Covid19-Data

In the course of a large-scale infectious disease a time-dependent Reproduction rate is an important parameter for political, economic and social decisions. In this paper we focus on that parameter and introduce a mathematical implementation in addition to the mostly used definition of Robert-Koch-Institute (RKI) in Germany. Such value is of particular interest in order to serve as a criterion for possible Lock-Downs and "LockUps" in society and can provide deep insights into a pandemic event. Both the definition of the new Reproduction index and the RKIs Reproduction number are compared analytically, applied to simple model calculations and finally on real Covid19 data. Clear advantages of the new Reproduction index become apparent and some weaknesses of the RKIs Reproduction number become clearly visible. In addition we propose two additional ways of displaying pandemic data to have the pandemic behaviour at a glance. We find that some signatures of the pandemic appear now very well expressed - especially in conjunction with the new Reproduction index Ri. This all could be very helpful for future political, social and economic decisions.

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole.

BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17.

BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

Prediction of node-negative breast cancer outcome by histologic grading and S-phase analysis by flow cytometry: an Eastern Cooperative Oncology Group Study (2192).

Histologic evaluation and reporting of invasive breast cancer has effectively used Nottingham combined histologic grade (NCHG). This approach to predict outcome in invasive breast cancer has not been tested in multicenter cooperative trials. Histologic slides from selected breast cancer cases entered on node-negative Eastern Cooperative Oncology Group trials were assigned grades. Two pathologists evaluated cases for NCHG defined from differentiation, mitotic index, and nuclear grade. The study population consisted of separate samples from low- and high-risk strata, where low risk was estrogen receptor positive with a tumor size of less than 3 cm and high risk was estrogen receptor negative or tumor size greater than or equal to 3 cm. The rate of agreement was generally good, with 80% of cases classified the same for mitotic count and 76% of the cases classified the same for combined grade. There were no cases disagreeing from the lowest to the highest of the three categories. The median follow-up is 11.6 years, but for analysis of survival, this was truncated at 5 years. Mitotic index and combined grade as assessed by both pathologists showed significant associations with survival. High combined histologic grade was predictive for response to cyclophosphamide/methotrexate/5-fluorouracil (CMF) with survival differences at 5 years of 30% in the treated high-grade patients over the untreated patients. Overall, it is clear that pathologists can have close agreement in assignment of combined histologic grades, with highly significant prediction in univariate and borderline significance in multivariate analysis in prognostication of time to recurrence as well as survival. Thus, stratification used in these trials was highly prognostic as hoped, leaving a role for histologic grading in these relatively large tumors, more powerful than S-phase analysis in this series. In the subgroups of high-risk patients randomized between CMF and observation, there was a suggestion that the high-combined-grade group was predictive of treatment efficacy. We conclude that a combined histologic grade with defined criteria may be reliably assigned by practiced pathologists using readily available criteria, and that the measure may be of use in prognostication and prediction of therapeutic responsiveness when done in a technically ideal fashion.

21-day oral etoposide for metastatic breast cancer: a phase II study and review of the literature.

Previous studies of etoposide for metastatic breast cancer commonly used bolus regimens given over a short period of time and included heavily pretreated patients. Results were poor. Chronic oral regimens would be expected to be superior to bolus doses based on pharmacologic studies and patients with less previous chemotherapy would be expected to have higher response rates. We studied the efficacy of oral etoposide at a dose of 50 mg/m2/day for 21 days of a 28-day cycle in good-risk patients with metastatic breast cancer. Healthy patients (Eastern Cooperative Oncology Group performance status 0, 1, or 2) who had not received chemotherapy for at least 1 year before study entry were selected for therapy. Thirty-four patients were entered; three patients were ineligible and one was cancelled. Thirty patients were available for analysis of response. One complete response and eight partial responses were documented (response rate, 30%; 95% confidence interval, 15-49%). A higher response rate was observed in those patients who never received chemotherapy compared with those who had received prior chemotherapy (57 vs. 6%, p = 0.004). There were two treatment-related deaths, both owing to myelosuppression and infection. We found long-term administration of oral etoposide to have a reasonable response rate for metastatic breast cancer (30%). Our response rate was comparable to those of other published studies of long-term oral etoposide regimens for metastatic breast cancer. Response rates in single-arm studies have generally been higher for long-term oral regimens than those for bolus regimens. We also found the regimen to be significantly toxic, an observation that may be underemphasized in the earlier literature.

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Role of postmastectomy radiotherapy: A medical oncology perspective.

Current practice in the management of patients who undergo a mastectomy does not usually include radiotherapy. Data from both meta-analyses and two randomized studies challenge this approach. Part of the skepticism about postmastectomy radiotherapy is what biological rationale would justify this intervention. Hellman has proposed the spectrum hypothesis, which explains the potential indication for additional local therapy for such patients. Another concern is the risk for increased toxicity, especially cardiotoxicity in patients who receive anthracycline-based adjuvant regimens. The addition of new agents (eg, Herceptin) also requires careful monitoring with regard to toxicity. Furthermore, the timing of radiation with chemotherapy is problematic. Overall, there is now evidence to support a role for postmastectomy radiotherapy, but further studies are needed on how best to incorporate this modality in multimodality treatment of early-stage breast cancer.

A comparison of efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression.

A randomized, double-blind, multicenter study in 181 afebrile cancer patients with ANC levels < 500/microL receiving myelosuppressive chemotherapy was undertaken to compare sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the treatment of chemotherapy-induced myelosuppression. Patients received daily subcutaneous (SC) injections of either agent until ANC levels reached at least 1500/microL. There was no statistical difference between treatment groups in the mean number of days to reach an ANC of 500/microL, but the mean number of days to reach ANC levels of 1000/microL and 1500/microL was approximately one day less in patients receiving filgrastim. Fewer patients in the sargramostim arm were hospitalized, and they had a shorter mean length of hospitalization, mean duration of fever, and mean duration of i.v. antibiotic therapy compared with patients who received filgrastim. Both growth factors were well tolerated. No patient was readmitted to the hospital after growth factor was discontinued. Sargramostim and filgrastim have comparable efficacy and tolerability in the treatment of standard-dose chemotherapy-induced myelosuppression in community practice.

Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study.

PURPOSE: To compare failure-free survival (FFS) and overall survival (OS) for patients with metastatic breast cancer treated with the gonadotropin-releasing hormone (GN-RH) agonist, goserelin versus surgical ovariectomy. PATIENTS AND METHODS: Between August 1, 1987 and July 15, 1995 138 (136 eligible) premenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive metastatic breast cancer were entered by the Southwest Oncology Group (SWOG), North Central Cancer Treatment Group (NCCTG), and Eastern Cooperative Oncology Group (ECOG). Prior chemotherapy or hormone therapy for metastatic disease was not allowed. Patients were randomly assigned to goserelin (3.6 mg subcutaneously every 4 weeks; (n = 69) versus surgical ovariectomy (n = 67). The study was initially designed as an equivalence trial with 80% power to rule out a 50% improvement in survival due to ovariectomy. However, accrual was slow and the study was terminated early, which resulted in a final power of 60% for the alternative hypothesis of equal survival distributions. RESULTS: FFS and OS were similar for goserelin and ovariectomy. The goserelin/ovariectomy death hazards ratio was .80 and the associated 95% confidence interval (CI) was .53 to 1.20. The test of 50% improvement in survival due to ovariectomy was rejected at P = .006. Goserelin lowered serum estradiol to postmenopausal levels. Hot flashes (75% v 46%) and tumor flare (16% v 3%) were more common with goserelin. CONCLUSION: Goserelin and ovariectomy resulted in similar FFS and OS. We can rule out a moderate advantage for ovariectomy. Goserelin was safe and well tolerated.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

Randomized trial comparing the tolerability of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in cancer patients receiving myelosuppressive chemotherapy.

A prospective, randomized, double-blind, multicenter study in cancer patients receiving myelosuppressive chemotherapy was undertaken to evaluate and compare the tolerability of sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the prophylaxis or treatment of chemotherapy-induced neutropenia. In all, 137 evaluable patients received sargramostim (300 micrograms; 193 mg/m2) or filgrastim (481 mg; 7 mg/kg) once daily by self-administered s.c. injection, usually beginning within 48 h after completion of chemotherapy. With the exception of a slightly higher incidence of grade 1 fever (< 38.1 degrees C) with sargramostim, there were no statistically significant differences in the incidence or severity of local or systemic adverse events possibly related to the growth factors. Although the study was not designed to evaluate efficacy directly, there also were no statistically significant differences between treatment groups in total days of growth factor therapy, days of hospitalization, or days of i.v. antibiotic therapy during the treatment period. Both sargramostim and filgrastim were comparably well tolerated when given by s.c. injection in this group of patients, and no clinically significant differences between the growth factors were demonstrated.

Phase II trial of biweekly paclitaxel and cisplatin in advanced breast carcinoma: an Eastern Cooperative Oncology Group study.

PURPOSE: To determine the efficacy of a biweekly paclitaxel and cisplatin regimen in patients with advanced breast carcinoma, which has previously been reported to produce an 85% response rate in such patients. PATIENTS AND METHODS: Sixteen patients with metastatic breast carcinoma who had relapsed after prior doxorubicin-containing adjuvant chemotherapy were treated with paclitaxel (90 mg/m2) by intravenous (i.v.) infusion over 3 hours followed by cisplatin (60 mg/m2) given by i.v. infusion over 1 hour on an outpatient basis. Treatment was repeated every 2 weeks if the absolute neutrophil count was > or = 750/microL and platelet count > or = 75,000/microL. After a maximum of eight cycles of paclitaxel/cisplatin, patients received biweekly paclitaxel alone (90 mg/m2 with dose escalation). Thirteen patients were assessable for response and all for toxicity. Nine of 13 patients assessable for response (69%) had at least three sites of metastases and 10 patients (77%) had visceral-dominant disease. RESULTS: Partial response occurred in three of 13 assessable patients (23%; 90% confidence interval, 7% to 49%). All responders had two or fewer sites of metastases. The median time to progression was 4.3 months and the median survival duration was 11.4 months. Patients received a median of seven cycles of therapy (range, two to 21). Severe and/or life-threatening toxicity occurred in 50% and 38%, respectively, and consisted primarily of granulocytopenia, anemia, and neuropathy. The trial was terminated after the first interim analysis as per its two-stage design, since it was unlikely that the response rate would exceed 70%. CONCLUSION: Biweekly paclitaxel/cisplatin is not likely to produce a response rate greater than 70% in patients with metastatic breast cancer who have relapsed after prior doxorubicin-containing adjuvant chemotherapy and who have multiple sites of metastases and/or visceral-dominant disease.

Clinical efficacy of tamoxifen.

In 1977, tamoxifen, a nonsteroidal antiestrogen, was approved in the United States for the management of advanced breast cancer in postmenopausal women. Since that time, tamoxifen's therapeutic role has grown to include management of advanced breast cancer in premenopausal women, systemic adjuvant therapy for early breast cancer in premenopausal and postmenopausal women, and treatment of breast cancer in men; the drug is now being studied in chemoprevention trials for women at high risk for breast cancer. Tamoxifen therapy prolongs disease-free survival and reduces mortality in premenopausal, postmenopausal, node-positive, and node-negative patients. Positive objective responses are more frequent in patients with estrogen receptor-positive tumors. The role of tamoxifen in combination with chemotherapy needs to be further clarified with respect to the optimal regimen, sequential vs concomitant therapy, and appropriate patient selection. While the optimum duration of tamoxifen therapy has not yet been established, tamoxifen remains a major therapeutic agent in the medical management of breast cancer.

Adjuvant therapy in breast cancer.

Adjuvant therapy has a positive impact in both premenopausal and postmenopausal women with primary breast cancer. Some general principles can be used in making treatment decisions; however, the precise role of adjuvant treatment in breast cancer remains unclear in most clinical settings. Prognostic factors are discussed, along with information on uses of chemotherapy and tamoxifen.

Management of recurrent breast cancer.

A major challenge for the clinician in treating patients with metastatic breast cancer is to achieve the best tumor response with the least toxicity. A number of different clinical situations present, and several options for interventions are available. In addition, patients with metastatic disease are candidates for newer approaches. Currently, intensive chemotherapy with the potential goal of cure has been enthusiastically received; however, in most patients, the goal is palliation. Achieving this goal requires an understanding of the natural history of breast cancer and of the patient and her needs.

Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection.

BACKGROUND: A prospective study was initiated to explore an approach of limited therapy in elderly patients with early clinical stage breast cancer. METHODS: Between 1982 and 1989, 73 women with American Joint Committee on Cancer Stage I/II, clinically negative axillary lymph nodes aged 65 years or older (median age, 74 years) were enrolled in a treatment program consisting of tumor excision, breast and regional lymph node irradiation, and, in 66 patients, tamoxifen. Patients were assessed for disease outcome and complications. RESULTS: At a median follow-up of 54 months, 8-year rates of local and regional lymph node control were 92.5% and 100%, respectively. Eight-year probabilities of disease free, overall, and breast cancer specific survival were 84%, 52.5%, and 93.8%, respectively. There was minimal morbidity associated with either regional irradiation or tamoxifen. CONCLUSIONS: An approach to early breast cancer in the elderly that seeks to limit the aggressiveness of local and systemic therapies appears to result in a satisfactory disease outcome with few complications.