No breast cancer subgroup can be spared postoperative radiotherapy after breast-conserving surgery. Fifteen-year results from the Swedish Breast Cancer Group randomised trial, SweBCG 91 RT.

BACKGROUND: Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients. PATIENTS AND METHODS: A total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 years and thereafter referred to the Swedish mammography screening program. RESULTS: After 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P<0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P=0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P=0.68, nor was breast cancer-specific mortality significantly higher. CONCLUSIONS: RT after BCS significantly reduced the incidence of IBTR at 15 years of follow-up. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systemic therapy are needed to omit RT after BCS.

Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy.

BACKGROUND: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. PATIENTS AND METHODS: Five hundred and twenty-five women below the age of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. RESULTS: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). CONCLUSION: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS.

C-erbB-2 expression does not predict response to docetaxel or sequential methotrexate and 5-fluorouracil in advanced breast cancer.

Breast cancer patients with c-erbB-2-positive tumours seem to benefit from anthracycline-based adjuvant chemotherapy. The predictive value of c-erbB-2 for taxane sensitivity is not yet clear. The purpose of this study was to assess whether c-erbB-2 expression is associated with clinical sensitivity to docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). A total of 283 patients with metastatic breast cancer were initially enrolled in a randomised multicentre trial comparing docetaxel with sequential MF in advanced breast cancer. Paraffin-embedded blocks of the primary tumour were available for 131 patients (46%). c-erbB-2 status was determined by immunohistochemistry using a polyclonal antibody to the c-erbB-2 protein. C-erbB-2 expression was scored in a semi-quantitative fashion using a 0 to 3+ scale. Staining scores 2+ or greater were considered positive. Response evaluation was performed according to World Health Organization (WHO) recommendations. Overall 54 (42%) patients had c-erbB-2-positive tumours. There was no association between treatment outcome and c-erbB-2 overexpression. The overall response rates (RR) (n=128) among c-erbB-2-negative and -positive patients were 35 and 44%, respectively (P=0.359). In the MF arm (n=62), the RR was somewhat higher in the c-erbB-2 overexpressors (33% versus 18%, P=0.18). In the docetaxel arm the RRs were very similar, regardless of the c-erbB-2 expression (53% versus 53%). While several studies have suggested a prognostic and putative predictive significance of c-erbB-2 overexpression in early breast cancer, the significance of c-erbB-2 expression as a predictive factor for response to various cytotoxic treatments in advanced breast cancer is still controversial. In this study, c-erbB-2 expression could not predict response to either MF or T. Thus, tumours over-expressing c-erbB-2 are not uniformly more sensitive to taxanes and c-erbB-2 expression cannot yet be applied clinically as a predictive factor for response in advanced breast cancer.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.

BACKGROUND: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Multimodality treatment of 128 patients with locally advanced breast carcinoma in the era of mammography screening using standard polychemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide: prognostic and therapeutic implications.

BACKGROUND: Locally advanced breast carcinoma is associated with a poor prognosis. With single treatment modalities, i.e., surgery and/or radiation therapy, results have been consistently dismal. However, several earlier reports have indicated improvement in survival with a combined modality approach, i.e., the utilization of systemic therapy. METHODS: Between 1991 and 1994, 128 patients with locally advanced noninflammatory or inflammatory breast carcinoma (LABC) were treated with a combined modality strategy consisting of 4-6 courses of preoperative 5-fluorouracil (600 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) (FEC) every 3 weeks, followed by modified radical mastectomy or sector resection with axillary dissection in combination with postoperative radiotherapy and concomitant cyclophosphamide (850 mg/m2). Postoperatively, 3-5 adjuvant courses of FEC therapy were given. Nine percent of the patients received preoperative radiotherapy because the FEC therapy was not sufficiently effective. One-third of the patients were given tamoxifen (20 or 40 mg daily) at the end of the multimodal therapy. RESULTS: Clinical responses were observed in 60% of the patients; 5% had complete responses (CR) and 55% had partial responses (PR). Stable disease (SD) was observed in 40%. No patient had progressive disease (PD) preoperatively. With a median follow-up of 37 months, the median disease free survival (DFS) and median overall survival (OS) were 29 and 54 months, respectively. The actuarial 5-year DFS and OS were 36% and 49%, respectively. The locoregional recurrence rate was 20%, and 53% of the patients experienced systemic relapse. Univariate analysis revealed a significant prognostic difference according to clinical stage of LABC in favor of less advanced stages. Clinical and biologic parameters linked to a significantly worse prognosis were the presence of inflammatory breast carcinoma and peau d'orange. There was a significant trend of worse prognosis for patients receiving below 60% and 75% of the intended dose intensity with reference to DFS and OS, respectively. CONCLUSIONS: Standard dose preoperative and postoperative FEC therapy combined with surgery and radiotherapy in the era of mammography screening seem to yield results comparable to those achieved with other conventional strategies in the treatment of unscreened populations.

Dosage of adjuvant G-CSF (filgrastim)-supported FEC polychemotherapy based on equivalent haematological toxicity in high-risk breast cancer patients. Scandinavian Breast Group, Study SBG 9401.

BACKGROUND: Conventional dosages of cytostatics in mg/m2 will cause marked variations in systemic exposure, resulting in over- and under-treatment, at least with respect to side effects. PATIENTS AND METHODS: We are conducting a randomized adjuvant study for breast cancer patients younger than 60 years of age with > or = 70% risk of recurrence within five years. The first 89 consecutive patients who have received nine courses q three weeks of individually dose-escalated and G-CSF (filgrastim)-supported FEC (5-fluorouracil (5-FU), epirubicin, and cyclophosphamide) therapy given with ciprofloxacin prophylaxis were included in this analysis. Six different FEC dose levels were used for treatment at equivalent haematological toxicity. Dose modifications were based on white blood cell and platelet counts on days 8, 11/12, 15, and 22. RESULTS: Eighty-three of 89 patients completed all nine courses. The median epirubicin and cyclophosphamide doses were 782 mg/m2 (range 0-994 mg/m2) and 10.330 mg/m2 (range 0-14.460 mg/m2), respectively. Patients treated at the two highest dose levels experienced NCl grade 0 or 1 toxicities in 73% to 92% of the courses. Three patients have developed acute myeloid leukaemia, and two of them have demonstrated abnormalities compatible with topoisomerase II-poison-related karyotypic changes. CONCLUSIONS: Tailored adjuvant G-CSF-supported FEC polychemotherapy will make it possible for all patients to be treated at equivalent levels of haematological toxicity with significantly higher doses without a marked increase in other organ toxicities.

Combined systemic chemotherapy and irradiation of muscle-invasive transitional cell carcinoma of the urinary bladder.

A phase II study is presented, which encompasses the period June 1987 until July 1993, and includes 53 patients with muscle-invasive bladder cancer T2-4b who, due to age and/or poor health (37 cases) or primarily extensive lesions (18 cases), were considered inoperable and for whom treatment with neoadjuvant chemotherapy (cisplatin/methotrexate/leucovorin rescue) and radical irradiation was planned. The total number of intended chemotherapy courses could be delivered without undue toxicity to 46 patients (83%) and 44 subsequently underwent radiotherapy: this modality was, by and large, well tolerated. The primary transurethral resection and chemotherapy produced an objective response in 62% of the 53 patients and in 75% of the 44 evaluable patients. The combined programme produced an objective response in 83% of the 37 evaluable patients, 71% in the 44 patients who completed the combined programme and in 59% of the total group of 53 patients. The follow-up ranged from 3 to 62 months. Radiotherapy increased the total objective response rate, proving effective in approximately 50% of patients who did not respond to chemotherapy. The results of this study are regarded as promising and pave the way for a phase III trial.

A controlled study of low and high volume anesthetic jelly as a lubricant and pain reliever during cystoscopy.

To evaluate the influence of the volume of 2% lidocaine jelly as an anesthetic during cystoscopy 241 men and women received either 11 or 20 ml. jelly intraurethrally in a randomized, double-blind fashion. Pain was recorded on a visual analogue scale by the patient and on a 3-level scale by the physician. The pain scores according to the visual analogue scale were significantly higher in the patients given 11 ml. jelly than in those given 20 ml. when all patients in the study were analyzed. There was no significant difference in the visual analogue scale between the 2 treatments in women but a significant difference was noted in men, although in men older than 55 years the difference was not statistically significant. There was general agreement between the visual analogue scale results and the physician scores but the visual analogue scale procedure was more sensitive in detecting differences between treatments. It is suggested that approximately 11 ml. 2% lidocaine jelly is the appropriate volume for women and 20 ml. is the appropriate volume for men during cystoscopy but that the lower volume of jelly may be sufficient in older men.

An agenda for meeting the special needs of multiple birth families.

Over 80,000 multiple birth babies are born each year in the U.S. Their families must cope with a constellation of complex physical and psychosocial challenges, which jeopardizes their health and functioning. The demands of twin pregnancy and the parenting of twins, triplets, quadruplets, quintuplets or more puts these families at disproportionately high risk for infant mortality, birth defects, child abuse, substance abuse, financial problems and marital problems. Health and social service resources must be developed to alleviate the stresses associated with multiple birth and to empower parents to cope well. Guidelines for policies, parent education, professional training and service delivery developed for the California Department of Health Service, Maternal and Child Health Branch, are here offered for the consideration of policy makers and public health planners.