To evaluate the efficacy of postmastectomy radiotherapy (RT) combined with adjuvant chemotherapy compared to adjuvant chemotherapy alone as regards overall survival (OS), overall disease-free survival (ODFS), local disease-free survival (LDFS) and distant disease-free survival (DDFS).

We reviewed retrospectively two non-randomized groups of premenopausal high-risk breast cancer patients treated from 1985 to 1990 in the following Institutions: Department of Radiation Oncology of Brescia University, "Istituto del Radio O. Alberti" (IRA), and Department of Oncology of Brescia Hospital "Beretta Foundation" (BF). A total of 163 patients was found to satisfy the criteria of the current analysis: 81 patients received adjuvant chemotherapy alone [6 cycles CMF(1-8)] at BF and 82 patients received postoperative radiotherapy and chemotherapy [8 cycles CMF(1-21)] at IRA. A modified CMF schedule was chosen at IRA to avoid the feared increase in toxicity due to the association with RT. Primary surgical treatment was modified radical mastectomy with axillary node dissection in both cases.

A statistically significant improvement in OS was found in systemic adjuvant therapy patients compared to those also given RT (77.6% vs 59%; P = 0.0025). No statistically significant improvement in ODFS was found in the CMF(1-8) arm compared to the RT and CMF(1-21) stm: 51.6% vs 43.6%; P = 0.46. A statistically significant improvement in LDFS at 5 years was found in irradiated patients (89.3% vs 76.2%; P <0.05). The DDFS was also improved, although without evidence of statistical significance, in the CMF(1-8) group: at 5 years 65% vs 44% (P = 0.059).

The study confirmed that RT reduces the risk of local recurrence but without a statistically significant reduction in mortality. The lack of a survival benefit may somehow reflect the dose reduction in CMF(1-21). The evidence that CMF(1-8) offers undoubtable advantages over the CMF(1-21) regimen in OS and, perhaps, in distant control suggests that the dose intensity of CMF in this setting may also be important. In fact, although many CMF(1-8) patients received a dose intensity lower than 100%, 95% of them received a dose intensity higher than the maximum one of the CMF(1-21) patients. Although our results should be interpreted with caution, they seem to provide further rationale for testing the association of postoperative radiotherapy and the CMF(1-8) regimen in stage II breast cancer with positive nodes and treated with demolitive surgery, as already done in the conservative management of breast cancer, also in view of the new support therapies now available (i.e. hematologic growth factors).

There is no consensus on the optimal combination of systemic therapy and radiation therapy for patients with early-stage breast cancer treated with conservative surgery. This article reviews prospective and retrospective studies that shed light on this topic. Patients with positive, close, or unknown microscopic margins appear to benefit from relatively early initiation of radiation therapy, whereas those with wider tumor-free margin widths do not. For patients at high risk of distant failure (such as those with = 4 positive axillary nodes), chemotherapy may be more effective when it begins before radiation therapy rather than after. Regimens of concurrent radiation therapy and chemotherapy tend to have higher acute and subacute complication rates than sequential regimens, but the actual rates vary substantially with the exact details of the overall treatment program. There are no data on the impact of the timing of tamoxifen administration on the effectiveness of radiation therapy. Tamoxifen does not appear to increase complication rates relative to the use of radiation therapy alone. Thus, the best way of giving combined-modality therapy is uncertain. Further retrospective and prospective studies to investigate the issues discussed herein should be performed.

The nadir value of the absolute neutrophil count (ANC) in the first cycle of chemotherapy is an effective predictor of subsequent neutropenic events. This study was designed to validate an earlier published study based on a retrospective data analysis from a prospective randomized clinical trial.

The original published model was applied to a trial of 143 patients to cross-validate the model. We also tested the specification of the model on our data by using a logistic regression model with several variables, including first-cycle nadir ANC, age, menopausal status, hormone-receptor status, previous radiotherapy, and first-cycle decrease in hemoglobin concentration. Patients received fluorouracil, doxorubicin, and cyclophosphamide every 21 or 28 days for six cycles without hematopoietic support from colony-stimulating factor.

In the cross-validation analysis, the original model successfully classified patients by risk of neutropenic events (C = 0.78). When the model specification was tested, first-cycle nadir ANC was the sole significant (P < 0.0001) predictor of neutropenic events and the model had a good predictive power (C = 0.78). The estimated relative risk of 4.8 did not differ from the risk cited in the original model (P = 0.91). A significantly higher percentage of our patients with a low first-cycle nadir ANC of 0.25 x 10(9)/liter or less experienced febrile neutropenia (30% versus 10%, P = 0.04) and received at least 85% of the planned dose intensity (55% versus 32%, P = 0.05).

The original risk model used to predict neutropenic events was validated by our study. This information can be used to target high-risk patients for prophylactic treatment with filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) in chemotherapy cycles 2 to 6.

The objective of this study was to demonstrate how a clinical practice database can be used to illustrate the variations in adjunctive chemotherapy for breast cancer, to describe a measure of dose intensity (DI) to monitor that variation, and to design interventions to maximize a full-planned dose. An arbitrary sample of oncology practices across the United States was selected, each providing data on 10-20 patients treated with adjuvant chemotherapy for early-stage breast cancer. Data on 17,566 patients from 1,438 sites were collected, consisting of patient characteristics including age, number of positive nodes, planned and delivered chemotherapy agents, and a sample of absolute neutrophil or white blood cell counts by cycle. Mean age of the patient cohort was 48.5 years, and 54% of patients were below the age of 49. Treatment for the disease has changed during the 2 periods studied, 1983-1994 and 1995-1999. Use of Adriamycin/Cytoxan (AC) increased, whereas use of Cytoxan/Adriamycin/Fluorouracil (CAF) and full-dose Cytoxan/Methotrexate/Fluorouracil (CMF1) decreased. However, the less intense Cytoxan/Methotrexate/Fluorouracil combination (CMF2) has seen an actual increase in use during the 2 periods. Within the context of oncology care, including chemotherapy, full-dose intensive therapy and cure has always been the ultimate goal. In this study only 10% of the patients given AC received less than 85% of the full referenced dose, whereas about 20% of those receiving the other combinations fell into this category. Also, the summation dose intensity (SDI), a measure tying level of dose to survival, was highest in the AC group and lowest in the CMF2 group. Dose delays and dose reductions appear to account for the decrease in DI in the CMF1, CMF2, and CAF groups. DI, particularly SDI of adjuvant chemotherapy, which ties level of dose to survival in breast cancer patients, appears to be a reliable measure with which to assess the quality of care in community oncology practices. The 2 measures presented in this paper may be useful to managed care organizations for monitoring quality outcomes in this serious disease. Because one of the major reasons for reduction in chemotherapy dose appears to be neutropenia and its complications, these organizations can establish programs using DI as a basis for developing guidelines to optimize the clinical benefits of growth factors.

Variations in practice patterns are markers for the quality of patient care in general medicine, but little is known about variation in care delivered to cancer patients. This study's purpose was to describe chemotherapy use, variations in chemotherapy delivery, and the incidence of complications in community practice settings.

Data describing adjuvant chemotherapy for patients with early-stage breast carcinoma (ESBC) were collected from an ongoing Oncology Practice Pattern Study at 13 large managed care, academic, and community practices (1111 patients). Data collection included information about diagnoses and adjuvant chemotherapy treatments, laboratory results, supportive care, complications, and treatment modifications.

The median patient age was 50 years, and most patients had zero to three positive lymph nodes. Chemotherapy regimens consisting of cyclophosphamide, methotrexate, and 5-fluororacil (CMF) and of doxorubicin and cyclophosphamide (AC) accounted for 76% of the adjuvant therapies used. Overall, 30% of patients had delivered average relative dose intensities </= 85% of the referenced targets. Delivered summation dose intensities (SDIs) frequently were well below targeted SDIs. Neutropenia-related dose modifications occurred for 27.6% of patients and recurred with a 60.7% rate. AC was the regimen delivered with a dose intensity closest to the referenced target. However, patients who were treated with AC regimens and with regimens consisting of cyclophosphamide, doxorubicin, and 5-fluorouracil had significantly higher rates of chemotherapy-related complications compared with patients who were treated with CMF regimens in the most recent treatment years.

Adjuvant chemotherapy for patients with ESBC frequently is not administered as referenced in off-protocol community settings. Variation in the delivered SDI raises concerns about potential treatment outcomes and warrants strategies to identify patients who are at risk for complications early in therapy.

To establish the toxicity profile of simultaneously administered postoperative radiation therapy and CMF chemotherapy as a prelude to a randomized controlled study addressing the sequencing of the two modalities.

One hundred and thirty eight breast cancer patients at high risk of locoregional, as well as systemic relapse, who were referred to three centers in Australia and New Zealand were treated with postoperative radiation therapy and chemotherapy simultaneously. Acute toxicity and dose modifications in these patients were compared with 83 patients treated over the same time frame with chemotherapy alone. In a separate study the long-term radiation and surgical effects in 24 patients treated simultaneously with radiation therapy and chemotherapy at Newcastle (Australia) following conservative surgery were compared with 23 matched patients treated at Newcastle with radiation therapy alone.

Myelotoxicity was increased in patients treated simultaneously with radiation therapy and chemotherapy. The effect was not great, but may have contributed to chemotherapy dose reductions. Lymphopenia was observed to be the largest factor in total white cell depressions caused by the simultaneous administration of radiation therapy. Postsurgical appearances were found to so dominate long-term treatment effects on the treated breast that the effect of radiation therapy dose and additional chemotherapy was difficult to detect.

Studies addressing the sequencing of radiation therapy and chemotherapy will necessarily be large because adverse effects from administering the two modalities simultaneously are not great. The present study has endorsed the importance in future studies of stratification according to the extent and type of surgery and adherence to a single strict policy of chemotherapy dose modification.

The likelihood of radiation pneumonitis and factors associated with its development in breast cancer patients treated with conservative surgery and radiation therapy have not been well established. To assess these, we retrospectively reviewed 1624 patients treated between 1968 and 1985. Median follow-up for patients without local or distant failure was 77 months. Patients were treated with either tangential fields alone (n = 508) or tangents with a third field to the supraclavicular (SC) or SC-axillary (AX) region (n = 1116). Lung volume treated in the tangential fields was generally limited by keeping the perpendicular distance (demagnified) at the isocenter from the deep field edges to the posterior chest wall (CLD) to 3 cm or less. Seventeen patients with radiation pneumonitis were identified (1.0%). Radiation pneumonitis was diagnosed when patients presented with cough (15/17, 88%), fever (9/17, 53%), and/or dyspnea (6/17, 35%) and radiographic changes (17/17) following completion of RT. Radiographic infiltrates corresponded to treatment portals in all patients, and in 12 of the 17 patients, returned to baseline within 1-12 months. Five patients had permanent scarring on chest X ray. No patient had late or persistent pulmonary symptoms. The incidence of radiation pneumonitis was correlated with the combined use of chemotherapy (CT) and a third field. Three percent (11/328) of patients treated with a 3-field technique who received chemotherapy developed radiation pneumonitis compared to 0.5% (6 of 1296) for all other patients (p = 0.0001). When patients treated with a 3-field technique received chemotherapy concurrently with radiation therapy, the incidence of radiation pneumonitis was 8.8% (8/92) compared with 1.3% (3/236) for those who received sequential chemotherapy and radiation therapy (p = 0.002). A case:control analysis was performed to determine if the volume of lung irradiated (as determined using central lung distance [CLD]) was related to the risk of developing radiation pneumonitis. Three control patients were matched to each case of radiation pneumonitis based on age, side of lesion, chemotherapy (including sequencing), use of a third field, and year treated. Lung volumes were similar in the radiation pneumonitis cases and controls. We conclude that radiation pneumonitis following conservative surgery and radiation therapy for breast cancer is a rare complication, and that it is more likely to occur in patients treated with both a 3-field technique and chemotherapy (particularly given concurrently with radiation therapy). Over the limited range of volumes treated, lung volume was not associated with an increased risk of radiation pneumonitis.

With improved screening and education, a greater proportion of breast cancer is detected at an early stage. Although the prognosis for many of these patients is excellent following definitive local therapy alone, some subsets of node-negative patients have a 30% chance of eventually developing metastatic disease that will be incurable with current therapy. Thus, an increasing proportion of early-stage patients are being offered some form of adjuvant therapy, with the expectation of improved relapse-free survival, and possibly improved overall survival. Efforts have been made to base the selection of patients for adjuvant therapy on specific prognostic factors. Meanwhile, the scope and complexity of putative prognostic factors continues to widen, and now includes such items as the presence of occult microscopic metastases, DNA ploidy and proliferative fraction, cytogenetic abnormalities, oncogene expression, growth factor receptors, and expression of hormonally regulated proteins. In addition, there is now a considerable range of options with regard to the composition, dose intensity, and sequence of multimodality therapy. Data regarding the classification, significance, and interpretation of prognostic factors is reviewed together with the development, current status, and recommendations regarding adjuvant therapy for patients with early-stage breast cancer. For 1991, the National Cancer Institute (NCI) has estimated that 175,000 new cases of breast cancer will be diagnosed in American women. It is also estimated that 44,500 women will die of breast cancer. Unfortunately, the age-adjusted death rate from breast cancer has shown no overall change from 1930 through 1987. However, effective screening techniques continue to identify an increasing percentage of early-stage tumors, which should exceed 50% of all new tumors in 1991. Ultimately, our understanding of environmental and genetic risk factors may identify new ways to reduce the impact of this disease. In the interim, development and application of effective systemic adjuvant chemotherapy and hormonal therapy has become increasingly important. There is no question that a greater proportion of patients with less extensive disease are now being offered some form of adjuvant therapy. Meanwhile, selection of patients for adjuvant therapy, and choice among specific adjuvant regimens, has remained controversial. Analysis of multiple prognostic factors is performed not only in the context of cooperative investigational trials, but more often in the offices of individual physicians caring for individual patients. Tumor biopsies can now be routinely sent to specialized laboratories for performance of complex assays with potential prognostic information, although interpretation of these results with reference to a specific patient is often uncertain.(ABSTRACT TRUNCATED AT 400 WORDS)