Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944).

PURPOSE: To describe long-term results of a multimodality strategy for stage III breast cancer utilizing neoadjuvant doxorubicin followed by mastectomy, CMF, and radiotherapy. PATIENTS AND METHODS: Women with biopsy-proven, clinical stage III breast cancer and adequate organ function were eligible. Neoadjuvant doxorubicin (30 mg/m(2) days 1-3, every 28 days for 4 cycles) was followed by mastectomy, in stable or responding patients. Sixteen weeks of postoperative CMF followed (continuous oral cyclophosphamide (2 mg/kg/day); methotrexate (0.7 mg/kg IV) and fluorouracil (12 mg/kg IV) weekly, weeks 1-8, and than biweekly, weeks 9-16). Radiation therapy followed adjuvant chemotherapy. RESULTS: Clinical response rate was 71% (79/111, 95% CI = 62-79%), with 19% complete clinical response. Pathologic complete response was 5% (95% CI = 2-11%). Median follow-up is 15.6 years. Half of the patients progressed by 2.2 years; half died by 5.4 years (range 6 months-15 years). The hazard of dying was greatest in the first 5 years after diagnosis and declined thereafter. Time to progression and overall survival were predicted by number of pathologically involved lymph nodes (TTP: HR [10 vs. 1 node] 2.40, 95% CI = 1.63-3.53, P < 0.0001; OS: HR 2.50, 95% CI = 1.74-3.58, P < 0.0001). CONCLUSIONS: After multimodality treatment for locally advanced breast cancer, long-term survival was correlated with the number of pathologically positive lymph nodes, but not to clinical response. The hazard of death was highest during the first 5 years after diagnosis and declined thereafter, indicating a possible intermediate endpoint for future trials of neoadjuvant treatment.

Amendment effects on soil test phosphorus.

Applications of animal manures have increased soil test P values in many parts of the USA and thus increased the risk that soil P will be transferred to surface water and decrease water quality. To continue farming these areas, landowners need tools to reduce the risk of P losses. A field experiment was conducted near Kurten, TX, on a Zulch fine sandy loam (thermic Udertic Paleustalfs) with Bray-1 P values exceeding 3000 mg P kg(-1) soil (dry wt.) in the A(p) horizon to evaluate the effectiveness of soil amendments for reducing soil test P values. Soils were amended annually from 1999 to 2001 with 1.5 and 5.0 Mg gypsum ha(-1), 1.4 Mg alum ha(-1), or 24.4 Mg ha(-1) of waste paper product high in Al alone or in combination with 1.5 Mg gypsum ha(-1) and/or 1.4 Mg alum ha(-1). These treatments supplied a maximum of 225 and 1163 kg ha(-1) yr(-1) of Al and Ca, respectively. Soil Bray-1 P and dissolved reactive P levels were monitored from 1999 to 2004. None of the soil amendment treatments affected Bray-1 P values. Only annual additions of 5.0 Mg gypsum ha(-1) from 1999 to 2001 significantly reduced soil dissolved reactive P. Dissolved reactive P levels reached minimal levels after two applications of 5.0 Mg gypsum ha(-1) but increased in 2003 and 2004. These results indicate that soil dissolved reactive P levels can be reduced if sufficient amounts of gypsum were added to supply Ca in amounts similar to the soil test P values.

Effects of near-surface hydraulic gradients on nitrate and phosphorus losses in surface runoff.

Phosphorous (P) and nitrogen (N) in runoff from agricultural fields are key components of nonpoint-source pollution and can accelerate eutrophication of surface waters. A laboratory study was designed to evaluate effects of near-surface hydraulic gradients on P and N losses in surface runoff from soil pans at 5% slope under simulated rainfall. Experimental treatments included three rates of fertilizer input (control [no fertilizer input], low [40 kg P ha(-1), 100 kg N ha(-1)], and high [80 kg P ha(-1), 200 kg N ha(-1)]) and four near-surface hydraulic gradients (free drainage [FD], saturation [Sa], artesian seepage without rain [Sp], and artesian seepage with rain [Sp + R]). Simulated rainfall of 50 mm h(-1) was applied for 90 min. The results showed that near-surface hydraulic gradients have dramatic effects on NO(3)-N and PO(4)-P losses and runoff water quality. Under the low fertilizer treatment, the average concentrations in surface runoff from FD, Sa, Sp, and Sp + R were 0.08, 2.20, 529.5, and 71.8 mg L(-1) for NO(3)-N and 0.11, 0.54, 0.91, and 0.72 mg L(-1) for PO(4)-P, respectively. Similar trends were observed for the concentrations of NO(3)-N and PO(4)-P under the high fertilizer treatment. The total NO(3)-N loss under the FD treatment was only 0.01% of the applied nitrogen, while under the Sp and Sp + R treatments, the total NO(3)-N loss was 11 to 16% of the applied nitrogen. These results show that artesian seepage could make a significant contribution to water quality problems.

Invertebrate responses to the management of genetically modified herbicide-tolerant and conventional spring crops. I. Soil-surface-active invertebrates.

The effects of herbicide management of genetically modified herbicide-tolerant (GMHT) beet, maize and spring oilseed rape on the abundance and diversity of soil-surface-active invertebrates were assessed. Most effects did not differ between years, environmental zones or initial seedbanks or between sugar and fodder beet. This suggests that the results may be treated as generally applicable to agricultural situations throughout the UK for these crops. The direction of the effects was evenly balanced between increases and decreases in counts in the GMHT compared with the conventional treatment. Most effects involving a greater capture in the GMHT treatments occurred in maize, whereas most effects involving a smaller capture were in beet and spring oilseed rape. Differences between GMHT and conventional crop herbicide management had a significant effect on the capture of most surface-active invertebrate species and higher taxa tested in at least one crop, and these differences reflected the phenology and ecology of the invertebrates. Counts of carabids that feed on weed seeds were smaller in GMHT beet and spring oilseed rape but larger in GMHT maize. In contrast, collembolan detritivore counts were significantly larger under GMHT crop management.

Existential concerns in late stage cancer.

In health care, it is generally acknowledged that individuals experiencing cancer illness and dying of cancer face a challenging time. Oncology and palliative care have responded by developing an expertise of treatment and care. The opportunity to receive the best of health care is accepted as an important concern to patients. However, recent research explains that many areas of dying cancer patients' concerns remain undisclosed and unresolved (Heaven & Maguire 1997). The purpose of this qualitative study was to identify dying cancer patients' concerns with the aim of developing a Concerns Questionnaire to further explore the relationship between patients' concerns and psychological and physical distress. In-depth interviews were carried out with 21 patients with advanced cancer who had been told they were no longer to receive curative treatments. Content analysis of the interview transcripts showed that existential concerns were a significant issue for these patients. Furthermore, patients' opportunity for reflection, personal change and inner discovery at the end of their illness could be enhanced by earlier experiences of holistic cancer care.

HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer.

PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)-positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized-physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen. PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen-HER-2/neu status interactions and tamoxifen-p53 status interactions. RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen-HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome. CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.

erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer.

BACKGROUND: We have previously reported that high expression of the erbB-2 gene (also known as HER-2/neu and ERBB2) in breast cancer is associated with patient response to dose-intensive treatment with cyclophosphamide, doxorubicin (Adriamycin), and 5-flurouracil (CAF) on the basis of short-term follow-up of 397 patients (set A) with axillary lymph node-positive tumors who were enrolled in Cancer and Leukemia Group B (CALGB) protocol 8541. METHODS: To validate those findings, we conducted immunohistochemical analyses of erbB-2 and p53 protein expression in an additional cohort of 595 patients (set B) from CALGB 8541, as well as a molecular analysis of erbB-2 gene amplification in tumors from all patients (sets A and B). Marker data were compared with clinical, histologic, treatment, and outcome data. RESULTS: Updated analyses of data from set A (median follow-up, 10.4 years) showed an even stronger interaction between erbB-2 expression and CAF dose, by use of either immunohistochemical or molecular data. A similar interaction between erbB-2 expression and CAF dose was observed in all 992 patients, analyzed as a single group. However, for set B alone (median follow-up, 8.2 years), results varied with the method of statistical analysis. By use of a proportional hazards model, the erbB-2 expression-CAF dose interaction was not significant for all patients. However, in the subgroups of patients randomly assigned to the high- or the moderate-dose arms, significance was achieved. When patient data were adjusted for differences by use of a prognostic index (to balance an apparent failure of randomization in the low-dose arm), the erbB-2 expression-CAF dose interaction was significant in all patients from the validation set B as well. An interaction was also observed between p53 immunopositivity and CAF dose. CONCLUSIONS: The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further validated before clinical implementation. Interactions between erbB-2 expression, p53 expression, and CAF dose underscore the complexities of predictive markers where multiple interactions may confound the outcome.

Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B.

BACKGROUND: Both total dose and dose intensity of adjuvant chemotherapy are postulated to be important variables in the outcome for patients with operable breast cancer. The Cancer and Leukemia Group B study 8541 examined the effects of adjuvant treatment using conventional-range dose and dose intensity in female patients with stage II (axillary lymph node-positive) breast cancer. METHODS: Within 6 weeks of surgery (radical mastectomy, modified radical mastectomy, or lumpectomy), 1550 patients with unilateral breast cancer were randomly assigned to one of three treatment arms: high-, moderate-, or low-dose intensity. The patients received cyclophosphamide, doxorubicin, and 5-fluorouracil on day 1 of each chemotherapy cycle, with 5-fluorouracil administration repeated on day 8. The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had two thirds the dose intensity as the high-dose arm but the same total drug dose. Disease-free survival and overall survival were primary end points of the study. RESULTS: At a median follow-up of 9 years, disease-free survival and overall survival for patients on the moderate- and high-dose arms are superior to the corresponding survival measures for patients on the low-dose arm (two-sided P<.0001 and two-sided P = .004, respectively), with no difference in disease-free or overall survival between the moderate- and the high-dose arms. At 5 years, overall survival (average +/- standard error) is 79% +/- 2% for patients on the high-dose arm, 77% +/- 2% for the patients on the moderate-dose arm, and 72% +/- 2% for patients on the low-dose arm; disease-free survival is 66% +/- 2%, 61% +/- 2%, and 56% +/- 2%, respectively. CONCLUSION: Within the conventional dose range for this chemotherapy regimen, a higher dose is associated with better disease-free survival and overall survival.

Evolving concepts in the systemic drug therapy of breast cancer.

Experimental and clinical observations of the proliferation of cancer cells and their responses to cytotoxic drugs already have had an impact on the design of anticancer therapies and it is possible that further understanding of the natural history of tumors will enable better treatments to be developed. This review addresses several approaches to improving the prognosis for patients with breast cancer in which our understanding of tumor dynamics plays an important role. Increasing dose intensity can be achieved by dose escalation (increasing the amount of drug) or increasing dose density (reducing the time between treatments). The Gompertzian model of tumor growth, which is concordant with many experimental and clinical observations, can offer an explanation why, although dose escalation improves the number of clinical responses, cure is still uncommon. In the Gompertzian model, smaller tumors grow faster, so tumor regrowth between treatment cycles is more rapid when cell kill is greatest. Reducing the time available for tumor regrowth (increasing dose density), which is now possible through the use of colony-stimulating factors to hasten hematopoietic recovery, may have a greater impact on clinical outcome than dose escalation. Sequential schedules allow optimal doses to be used in dose-dense cycles. Several cycles of the optimal dose of agent A, followed by several cycles of the optimal dose of agent B, may be more effective than the simultaneous combination of suboptimal doses of A and B. In this context, agents A and B may be single agents or established combinations. This tactic allows new agents, such as the taxoids, to be used in conjunction with established therapies, such as doxorubicin plus cyclophosphamide, at optimal doses in dose-intensive regimens. Although such regimens may maximize cytoreduction, this may not be sufficient to improve significantly the long-term outcome for patients with breast cancer. A recent trial using high-dose consolidation chemotherapy with autologous bone marrow support has thrown doubt on the assertion, implicit in Gompertzian cytodynamics, that optimal cytotoxic therapy can kill all tumor cells. The results of this trial suggest that a consistent number of tumor cells remain whether high-dose chemotherapy with autologous bone marrow support is used in patients in complete pathologic remission or in patients with overt relapse. If there is a lower limit to cytoreduction, other approaches must be developed to control or prevent the regrowth of residual tumor cells. This will require a better understanding of the molecular biology of breast cancer and the ability to predict and assess the sensitivity of individual patient's tumors to particular therapies. Factors such as HER2 overexpression are already being linked to sensitivity to particular agents and the products of oncogenes such as HER2 may be targeted by biologic therapies such as monoclonal antibodies. Furthering our understanding of the biology and behavior of tumor cells may lead to significant improvements in the long-term prognosis for patients with early and advanced breast cancer.

Fish oil therapy in IgA nephropathy.

IgA nephropathy often progresses to endstage renal failure over a period of many years, and any therapy directed to IgA nephropathy will most likely have to be administered over an extended period of time. Therefore, optional therapy should be effective and free of long-term adverse effects. Besides fish oil, prednisone has also been investigated for treatment of IgA nephropathy, with a lack of consistent results; severe adverse effects are common with long-term use. Several studies have shown positive although not overly impressive results; therefore optimal therapy for slowing the progression of renal failure secondary to IgA nephropathy has not been established. Problematic issues with available studies included the following: (1) most of the clinical studies previously discussed were short-term, contained small numbers of patients, and most but not all were uncontrolled; (2) early reports involving fish oil therapy demonstrated conflicting results regarding its efficacy, including one study that observed increased progression of renal disease in patients treated with fish oil; however, recent studies have shown more promise for fish oil therapy for up to 2 years of treatment; and (3) since most of the studies were conducted over a short period of time, it is difficult to assess long-term effects and safety of oil treating IgA nephropathy, a disease that progresses to ESRD over 10-20 years. However, given the low number of adverse effects and apparent low risks associated with this relatively safe food supplement therapy observed in most clinical trials of up to 2 years duration, fish oil may slow the progression of renal failure in patients with IgA nephropathy. Therefore, with appropriate monitoring of renal function and blood tests, treatment with fish oil 6-12 g/d should be considered in patients with IgA nephropathy.

Adjuvant drug therapy for operable breast cancer.

Breast cancer-the most common malignancy of lethal potential for women in the developed world-presents as two interrelated problems: (1) local disease in the breast and axillary lymph nodes, and (2) micrometastatic disease in distant sites. During the last century, advances in surgery and radiotherapy have led to high rates of control over local disease. In addition, heightened public awareness and the more widespread use of mammography have led to the more frequent detection of smaller cancers with better prognosis. Nevertheless, the problem of distant recurrence, leading almost inevitably to death, persists. Hence, there is considerable interest in integrating systemic therapy, which since mid-century has been shown to be active against advanced disease, into the treatment of primary breast cancer. The long-standing theoretical prediction of benefit from drug therapy as an adjunct to local control procedures has now been confirmed by several decades of clinical investigation. Long-term follow-up of seminal trials and the conduct of a crucial series of meta-analyses have established the ability of both hormonal therapies and chemotherapy to prolong disease-free and overall survival in nearly all groups of patients. Although the relative and absolute influences of drug therapies remain modest, if these were properly applied to the hundreds of thousands of patients diagnosed worldwide per year, the potential impact on public health would be significant. In addition, recent laboratory advances and clinical trial data have indicated several new directions that promise greater impact against occult disseminated disease. These include novel dosing and scheduling strategies, newer active agents, fresh biochemical targets, and different combinations of chemotherapy with hormonal therapy.

Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study.

PURPOSE: To compare two cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) regimens with a doxorubicin-based regimen--vinblastine, doxorubicin, thiotepa, and Halotestin (Upjohn, Kalamazoo, MI) (VATH)--in patients with stage II node-positive breast carcinoma. METHODS: Nine hundred forty-five women were treated with a 6-week induction course of CMFVP. They were then randomized to receive one of two consolidation CMFVP regimens: 6-week courses or 2-week courses. Following completion of CMFVP consolidation, patients were again randomized to either continue the CMFVP regimen or to receive six escalating doses of VATH. RESULTS: Among all patients, with a median follow-up time of 11.5 years, there is no statistically significant difference in disease-free survival (DFS) between the two consolidation CMFVP regimens. VATH intensification treatment is statistically significantly superior to CMFVP in terms of DFS (P = .0040). For patients with one to three involved nodes, there is currently no significant difference between VATH and CMFVP; however, among those with four or more positive lymph nodes, there is a significant difference in favor of VATH (P = .0037). There is also improved overall survival with VATH (P = .043; median, > 14 years v 10 years). This difference is also statistically significant in patients with four or more involved lymph nodes, among postmenopausal patients, and among postmenopausal estrogen receptor-positive patients. CONCLUSION: Chemotherapy with crossover to escalating doses of VATH following CMFVP was well tolerated and effective. Inauguration of VATH as a treatment intensification at the eighth month produced a major increase in relapse-free and overall survival. The observation that sensitivity to VATH is retained so long after mastectomy raises questions about the proper duration of adjuvant chemotherapy and lends support to further investigation of cross-over designs in future trials to postoperative adjuvant chemotherapy regimens.

Sequential adjuvant therapy: the Memorial Sloan-Kettering Cancer Center experience.

Adjuvant chemotherapy has a real but modest impact on the disease-free and overall survival of patients with breast cancer. Recent attempts to improve its effectiveness have focused on dose intensity and new agents. Sequential therapy maximized dose intensity while limiting overlapping toxicity. Sequential therapy using doxorubicin followed by cyclophosphamide/methotrexate/5-fluorouracil (CMF) has been found superior in patients with high-risk resectable breast cancer. The novel chemotherapy agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is now known to be highly active in advanced breast cancer and appears to be clinically non-cross-resistant with doxorubicin. Therefore, this drug is being studied as a component of the next generation of adjuvant chemotherapy regimens. The most appropriate way to incorporate paclitaxel has not yet been defined, but its concurrent administration with other agents has, in some cases, been troublesome. Based on the demonstrated advantage of the sequential plan for doxorubicin and CMF, we conducted a series of pilot trials testing sequential high-dose therapy. Initially, we studied multiple cycles of doxorubicin followed by cyclophosphamide; we later added paclitaxel to this regimen. These phase II studies demonstrate the feasibility of sequential therapy with doxorubicin, paclitaxel, and cyclophosphamide, and early disease-free survival results are promising. Cooperative group projects are under way or planned to further define the activity of these regimens.

Complementary therapies in practice: the ethical issues.

This article explores some of the ethical issues associated with the use of complementary therapies in practice. The adopted terminology and related concepts are clarified. The term 'complementary therapy' is compared and contrasted with 'alternative medicine' and 'non-conventional therapy'. The increasing emphasis on holistic nursing care is also discussed. Ethical issues of patient choice, informed consent and the principle of beneficence are examined in relation to complementary therapies. The article highlights the obligation of the nurse, midwife or health visitor to provide or facilitate holistic care including complementary therapies, such as massage or aromatherapy, for those clients who request such care, and where it can be demonstrated that there will be benefits for the patient. It is concluded that nurses should consider the possibility of incorporating or facilitating certain complementary therapies in their practice in order to benefit their patients. There is a corresponding need for an appropriate knowledge base, founded on nursing research, into the effectiveness and outcomes of complementary therapies. In addition, relevant educational courses should be developed.

The effect of electrical perturbation on osseointegration of titanium dental implants: a preliminary study.

PURPOSE: Successful osseointegration of titanium dental implants is decreased in areas of poor bone volume and density. Low amperage direct current (LADC) has been shown to perturb bone cells, which in turn promotes bone growth. The purpose of this experiment was to evaluate the effect of LADC on the osseointegration of endosseous titanium dental implants. MATERIALS AND METHODS: Two implant sites were prepared in the body of the mandible of five rabbits by an extraoral approach. An LADC-stimulated 3.75 x 7 mm-titanium implant was placed in one site and an identical control implant was inserted on the contralateral side. A sterilized silicone-encased power pack producing 7.5 +/- 0.2 uA and 1.35 +/- 0.01 V was placed in a submandibular pouch. The active cathode lead was attached to the LADC implant and the anode was placed in the mandible 5 mm distal to the implant. Nonactive leads were similarly connected to the control implant. Twenty-eight days after placement, the implants were removed using a torque wrench, and the bone surrounding the implants was examined both microscopically and radiographically. RESULTS: The average force to initial rotation was 1,320 +/- 880 g/cm for the LADC-stimulated implants and 1,290 +/- 238 g/cm for the control implants. This was significantly different by t test (P = .94). Light microscopic evaluation demonstrated a mixture of compact and woven bone and fibrous tissue adjacent to both groups of implants. Histomorphometric analysis demonstrated an average percent of bone in relation to the total tissue adjacent to the control implants of 33.5 +/- 15.4 and 40.2 +/- 4.8 for the LADC-stimulated implants (not significantly different, t test, P = .39). CONCLUSION. It was concluded that LADC as used in this study does not positively affect the healing of bone. Its ability to enhance bone growth around titanium dental implants needs further investigation.

Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma.

BACKGROUND: Adjuvant chemotherapy is widely used for breast cancer and is known to extend survival. Some clinicians seek a greater survival benefit by increasing the intensity of the dose, whereas others lower it to diminish toxicity. METHODS: The Cancer and Leukemia Group B (CALGB) conducted a randomized trial of different levels of doses and dose intensity (dose per unit of time) of adjuvant chemotherapy in 1572 women with node-positive, stage II breast cancer who were assigned to three treatment groups. One group received 400 mg of cyclophosphamide per square meter of body-surface area and 40 mg of doxorubicin per square meter once every 28 days and 400 mg of fluorouracil per square meter twice every 28 days, for six cycles. Another group received 50 percent higher doses of the three drugs (600 mg, 60 mg, and 600 mg, respectively) but for only four cycles, so that the total dose was identical in these two groups but the dose intensity was higher in the first. The third group of women received half the total dose used in the other two groups and at half the dose intensity used in the second group. RESULTS: After a median of 3.4 years of follow-up, the women treated with a high or moderate dose intensity had significantly longer disease-free survival (P < 0.001) and overall survival (P = 0.004) than those treated with a low dose intensity, in three-way log-rank comparisons. However, the difference in survival between the two groups treated with a moderate or high dose intensity was not significant. These results are consistent with either a dose-response effect or a threshold level of the dose or dose intensity. CONCLUSIONS: The doses of chemotherapy used to treat breast cancer, especially early breast cancer, should not be reduced if the maximal benefit is to be achieved.

An intensive sequenced adjuvant chemotherapy regimen for breast cancer.

Twenty-two women (17 pre- and 5 postmenopausal) with nodepositive, stage II breast carcinoma were treated with adjuvant chemotherapy consisting of 16 weeks of intensive CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) administered in the original dose and schedule of the "Cooper regimen," followed by four monthly, 3-day cycles of escalating doxorubicin. Toxicity was related primarily to myelosuppression associated with the doxorubicin component of the treatment regimen. All patients recovered without sequelae. No patient developed significant cardiac toxicity. With a median follow-up of 43 months (range: 20-89 months), two postmenopausal patients and one premenopausal patient have relapsed at 35, 37, and 42 months, respectively. By Kaplan-Meier survival analysis, there is an 80.5% chance of disease-free survival to 42 months. The feasibility of administering adjuvant CMFVP followed by intensive doxorubicin has been established. The pilot results warrant comparative trial with the best of current regimens.

An experimental analysis of classically conditioned nausea during cancer chemotherapy.

This study investigated classical conditioning in women undergoing outpatient adjuvant chemotherapy for breast cancer. Breast cancer chemotherapy outpatients were randomly assigned either to an Experimental Group (exposed to a distinctive stimulus before each infusion of chemotherapy) or to a Control Group. After repeated infusions of chemotherapy, patients' responses to the experimental stimulus were assessed in a location not associated with chemotherapy. Experimental Group patients had increased nausea (self-reported on a visual analog scale) following the presentation of the experimental stimulus at this test trial, whereas Control Group patients did not. Two other measures of nausea corroborated these results. Post hoc statistical analyses confirmed predictions based on conditioning theory. This conditioning model of anticipatory nausea bears witness to the relevance of classical conditioning in clinical medicine.

Adjuvant systemic therapy for early breast cancer.

Systemic therapy (chemotherapy or hormonal therapy) as an adjuvant to modalities of local control is now an integral part of the management of almost all patients with primary breast cancer metastatic to axillary lymph nodes. In addition, recent data suggest an expanding role for such treatments in patients without axillary involvement. Although some node-negative patients should probably not receive adjuvant therapy, the precise criteria to be used for selection are still under active discussion in the literature. Of the two types of systemic treatment, it is generally accepted that chemotherapy is indicated for premenopausal patients and that tamoxifen is useful for postmenopausal patients whose tumors contain estrogen or progesterone receptors. The recent analysis of several studies has suggested that chemotherapy may add to the benefits of tamoxifen in some postmenopausal patients as well. A possible role for tamoxifen in younger patients is being evaluated. For patients at relatively low risk of systemic relapse (i.e., those with zero to three involved axillary lymph nodes), no chemotherapy regimen has yet shown an advantage over 6 months of cyclophosphamide, methotrexate and 5-fluorouracil. For patients at high risk, however, doxorubicin-based regimens have demonstrated benefits. High-dose chemotherapies, some involving autologous bone marrow support, are being investigated for patients with ten or more involved nodes who are at very high risk of the eventual development of stage IV disease.