Long-term outcome of pT1a-b, cN0 breast cancer without axillary dissection or staging: a prospective observational study of 1543 women.

BACKGROUND: The implementation of screening programmes in Sweden during the mid-1990s increased the number of small node-negative breast cancers. In this era before staging by sentinel node biopsy, routine axillary dissection for staging of early breast cancer was questioned owing to the increased morbidity and lack of perceived benefit. The long-term risk of axillary recurrence when axillary staging is omitted remains unclear. METHODS: This prospective observational multicentre cohort study included Swedish women diagnosed with breast cancer between 1997 and 2002. The patients had clinically node-negative, pT1a-b, grade I-II tumours. No axillary staging or dissection was performed. The primary outcome was ipsilateral axillary recurrence and survival. RESULTS: A total of 1543 patients were included. Breast-conserving surgery (BCS) was performed in 94·0 per cent and the rest underwent mastectomy. After surgery, 58·1 per cent of the women received adjuvant radiotherapy, 11·9 per cent adjuvant endocrine therapy and 31·5 per cent did not receive any adjuvant treatment. After a median follow-up of 15·5 years, 6·4 per cent developed contralateral breast cancer and 16·5 per cent experienced a recurrence. The first recurrence was local in 116, regional in 47 and distant in 59 patients. The breast cancer-specific survival rate was 93·7 per cent after 15 years. There were no differences in overall or breast cancer-specific survival between patients who received adjuvant radiotherapy and those who did not. Only 3·0 per cent of patients had an axillary recurrence, which was isolated in only 1·0 per cent. CONCLUSION: Axillary surgery can safely be omitted in patients with low-grade, T1a-b, cN0 breast cancers. This large prospective cohort with 15-year follow-up had a very low incidence of axillary recurrences and high breast cancer-specific survival rate.

ANTECEDENTES: La puesta en marcha en Suecia, a mediados de los años 90, de los programas de cribaje aumentó el número de cánceres de mama precoces con ganglios negativos. En esa era, antes de la estadificación mediante la biopsia del ganglio centinela, se cuestionó la disección axilar rutinaria para la estadificación del cáncer de mama precoz debido a su aumento de la morbilidad y la falta de percepción de beneficio. El riesgo de recidiva axilar a largo plazo cuando no se omite la estadificación axilar sigue sin estar claro. MÉTODOS: Estudio de cohortes prospectivo, observacional y multicéntrico de las mujeres suecas diagnosticadas de cáncer de mama entre 1997-2002. Se incluyeron las pacientes con ganglios clínicamente no detectables, pT1a-b, grados I-II y no se realizó disección/estadificación axilar en ninguna de ellas. El resultado principal fue la recidiva axilar ipsilateral y la supervivencia. RESULTADOS: Se incluyeron 1.543 pacientes. Se realizó cirugía conservadora de la mama (breast conserving surgery, BCS) en el 94% de las mujeres y en las restantes se practicó una mastectomía. Tras la BCS, el 58% de las mujeres recibió radioterapia adyuvante, el 12% tratamiento endocrino adyuvante y el 32% no recibió ningún tratamiento adyuvante. Tras una mediana de seguimiento de 15,5 años, el 6% desarrolló un cáncer de mama contralateral y un 14% una recidiva. La primera recidiva fue local en 116 pacientes, regional en 47 y a distancia en 59. La supervivencia específica para el cáncer de mama a los 15 años fue del 94%. No hubo diferencias en la supervivencia general o específica por cáncer de mama entre las pacientes que recibieron radioterapia adyuvante y las que no. Solo el 3% de las pacientes presentó una recidiva axilar, de las cuales tan solo el 1% padecieron exclusivamente una recidiva axilar. CONCLUSIÓN: La cirugía axilar se puede omitir con seguridad en los cánceres de mama de bajo grado, T1a-b, cN0. Esta gran cohorte prospectiva con un seguimiento de 15 años muestra que la incidencia de recidivas axilares es muy baja y la supervivencia específica por cáncer de mama muy alta.

Determinants of non-adherence to adjuvant endocrine treatment in women with breast cancer: the role of comorbidity.

PURPOSE: To examine factors associated with non-adherence during 5 years of endocrine treatment, including the possible influence of comorbidity burden and specific medical conditions. METHODS: From all women diagnosed with stage I-III, ER-positive breast cancer in Stockholm-Gotland, Uppsala-Örebro and Northern Sweden between 2006 and 2009, we included 4645 women who had at least one dispensation of tamoxifen or aromatase inhibitors (AIs) and 5 years of follow-up without distant recurrence. A medical possession ratio of < 80% was used to define non-adherence. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of non-adherence. RESULTS: During follow-up, 977 (21%) women became non-adherents. Non-adherence was associated with greater comorbidity burden assessed by Charlson comorbidity index (CCI) during follow-up (OR 1.43; 95% CI 1.08-1.88 for ≥ 2 additional scores compared to 0), pre-diagnostic HRT use (OR 1.99; 1.58-2.49), not married (OR 1.42; 1.23-1.64), high educational level (OR 1.25; 1.02-1.53 compared to lowest level), and use of symptom-relieving drugs. HER-2 positivity (OR 0.61; 0.45-0.81) and adjuvant chemotherapy (OR 0.42; 0.35-0.52) were associated with lower odds of non-adherence. Similar patterns were observed for the presence of lymph node metastasis, higher tumour grade, and use of AIs compared to tamoxifen. Myocardial infarction and chronic pulmonary disease was suggested as leading conditions associated with non-adherence in women with increasing CCI. CONCLUSION: We identified subgroups of women with breast cancer at increased risk of non-adherence. Our findings related to comorbidity suggest the importance of focusing on the presence of specific co-existing conditions when monitoring adherence.

Oncologists and hematologists' perceptions of fertility-related communication - a nationwide survey.

BACKGROUND: Despite the negative impacts of several cancer treatments on fertility, many patients do not recall having fertility-related discussions with their physicians. This study was conducted to identify those factors related to physicians' discussing the treatment impacts on fertility with cancer patients of reproductive age. MATERIAL AND METHODS: In this nationwide survey of cancer care physicians (n = 329, response rate 55%), oncologists and hematologists (mainly) completed a questionnaire on practice behavior, barriers, attitudes and confidence in knowledge regarding treatment-related fertility risks. Logistic regression analyses were conducted to identify factors associated with not routinely discussing fertility issues with patients. RESULTS: Most of the physicians agreed that they were responsible for discussing fertility issues with patients of reproductive age (91%), but approximately 30% did not do so regularly. Those factors decreasing the likelihood of discussion were: patient already had children (female/male OR 3.0/6.9), high workload (OR 3.3/4.8), seeing <5 female/male patients of reproductive age weekly (OR 3.2/3.4) and access to a reproduction clinic (OR 5.2/4.2). CONCLUSIONS: Most Swedish oncologists and hematologists regularly discuss impact of treatment on fertility with their patients. Those factors having a negative impact on fertility discussions may guide targeted organizational and educational efforts to further improve fertility-related communication in cancer care.

A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

STUDY AIM: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). METHODS: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). RESULTS: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. CONCLUSIONS: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

Repair of DNA alkylation induced in L1210 leukemia and murine bone marrow by three chloroethylnitrosoureas.

The removal of DNA adducts is an essential step of DNA repair following exposure to chloroethylnitrosoureas. Adduct removal was evaluated in both L1210 and murine bone marrow DNA for lesions induced by three chloroethylnitrosoureas. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, a marrow-toxic agent with high carbamoylating activity, was not removed in either system for at least 6 to 12 hr. These results were compared with those obtained with two glucose-linked chloroethylnitrosoureas, chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea. Both of these agents have low marrow toxicity at therapeutic doses. Chlorozotocin, which has very low chemical carbamoylating activity, was found to permit approximately 40% removal of drug-derived DNA adducts in both systems within the first 6 hr and approximately 50% by 18 hr. The second glucose-linked analog, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, has relatively high carbamoylating activity and was found to inhibit early removal of DNA adducts as effectively as does 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. It would thus appear that the selective marrow-sparing property of the sugar-linked chloroethylnitrosoureas is not dependent upon carbamoylation-mediated differences in the rate and extent of DNA adduct removal. In view of the comparable therapeutic activity of the three drugs for L1210 leukemia, therapeutic efficacy does not appear to be impaired by the increased rate of adduct removal observed with chlorozotocin in this system.

5-fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary.

The combination of 5-fluorouracil (5-FU), doxorubicin, and mitomycin (FAM) is often recommended for empiric management of patients with adenocarcinoma of unknown primary. This recommendation is based on the activity of FAM for adenocarcinomas of specific known sites of origin. A literature search disclosed no reports of the efficacy of FAM in this clinical entity. We report on 45 patients with biopsy-proven adenocarcinoma in whom investigation revealed no primary site and who were treated in a phase II trial with FAM. Of 43 evaluable patients, four achieved a complete tumor response, and nine obtained a partial response for an overall response rate of 30%. The median survival for all patients was greater than 10 months. The median survival for patients whose tumors were unresponsive to FAM was 6 months, and median survival was greater than or equal to 14 months in patients with stable disease or FAM-responsive tumors. A phase III trial comparing no therapy or 5-FU with FAM is warranted. For patients not treated in an investigative setting, FAM compares favorably with reported series using other regimens.

Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study.

An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide, doxorubicin, and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms, with four toxic deaths in each arm (4.7%). Response results were also similar, with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex, performance status 3, liver metastases, bone marrow metastases, and oat cell histologic subtype).

A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study.

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.

Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

PURPOSE: To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS: No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.

A study of infusional cisplatin and infusional fluorouracil for locally advanced or metastatic non-small-cell lung cancer: a Mid-Atlantic Oncology Program study.

A combination of cisplatin administered as a 24-hour infusion and fluorouracil administered as a 5-day infusion was used to treat 97 patients with non-small-cell lung (NSCLC) cancer in a phase II trial. Thirty patients had stage IIIB disease; 67 patients, stage IV disease (new international classification). Patients with stage IIIB disease also received thoracic radiation after chemotherapy. The regimen was well tolerated, with 24% or less grade 3 or greater toxicities of all types. One toxic death was attributed to fluid overload. The response rate, partial and complete, was 43% (95% confidence interval, 27% to 63%), and median survival was 13.8 months for patients with stage IIIB disease. Response rates refer to the chemotherapy response. For patients with stage IV disease, the response rate was 34% (95% confidence interval, 24% to 47%), and median survival was 6.2 months. On this regimen, stable-disease patients with stage IV disease had survivals at least equal to responders.

Angiogenesis in invasive breast carcinoma--a prospective study of tumour heterogeneity.

Assessment of angiogenesis has been reported to be an independent prognostic factor in breast cancer, while other studies have been negative. This study prospectively investigates the degree of intratumoral microvessel heterogeneity and the possible influence on the results. From 21 invasive breast cancers six 4 micro sections were cut. Sections (n=126) were stained immunohistochemically with a CD31 monoclonal antibody (JC70). In each section, three areas with the most intense neovascularisation (hot spots) were identified and the microvessel density (MVD) was obtained by counting vessels at 200x magnification. The variation between sections contributed more to the total variance than variation between different tumours: 45.0 and 37.3%, respectively, according to a nested ANOVA analysis. Paired comparisons of two sections at a time from the same tumour showed a concordance in 59.0% (95% Confidence Interval (CI): (55.3-62.8)) with reference to a tentative cut-off level. Our study demonstrates that assessment of MVD in hot spots is questionable to measure angiogenesis due to the considerable intratumoral heterogeneity.

Epidemiology and risk factors in pancreatic cancer.

Pancreatic cancer is one of the most lethal neoplasms. Incidence in the United States has remained fairly stable over the past 25 years, with about 25,000 cases annually. Almost 100% of cases are fatal. Incidence in the developed world parallels that in the United States. Incidence in undeveloped nations is lower but may be underreported. Worldwide incidence is about 185,000 cases per year. There are no striking environmental risk factors, and geographic variation is less than with other gastrointestinal cancers. The most significant risk appears to be cigarette smoking, with a risk ratio of about 2. Alcohol and coffee consumption have been reported as possible risks in some (but not in most) studies. Diet is probably a significant factor, but is difficult to evaluate quantitatively. Other putative associations, including diabetes, probably are unimportant.

Five-node biopsy of the axilla: an alternative to axillary dissection of levels I-II in operable breast cancer.

BACKGROUND: Axillary clearance of patients with early breast cancer is accompanied by a high risk of arm morbidity. Less invasive ways to establish the axillary nodal status are therefore of interest, especially in women with low risk of nodal metastases. METHODS: Four hundred and fifteen breast cancer patients (clinical stage T(0-3) N(0-1) M(0)) were operated in the axilla with a five-node biopsy followed in the same operation by a further dissection of levels I-II of the axilla in order to evaluate the accuracy of the five-node node biopsy compared with level I-II dissection. RESULTS: In all patients the sensitivity of the five-node biopsy was 97.3% with a negative predictive value of 98.5% and a negative likelihood ratio of 0.027. Among cases detected by screening (n=204) and those clinically detected (n=197) the sensitivity of the five-node biopsy was 95.8% and 97.9% respectively, with negative predictive values of 98.7% and 98.0% and negative likelihood ratios of 0.042 and 0.021 respectively. CONCLUSION: Five-node biopsy of the axilla has good accuracy for correctly staging the axilla in both clinically and screening-detected cases. Five-node biopsy is an alternative to axillary clearance and sentinel node biopsy in patients with operable breast cancer.

Dichloromethotrexate, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small cell lung cancer. A MAOP study.

The combination of dichloromethotrexate, cisplatin, and infusional 5-fluorouracil was evaluated as treatment for non-small-cell lung cancer in a phase II trial using 43 evaluable patients. Grade III or IV toxicity included thrombocytopenia (21%), leukopenia (14%), nausea/vomiting (14%), mucositis (9%), infection (5%), and other (16%). There were six responders (14%), with a 95% confidence interval of [5%, 28%]. Two additional patients achieved a 50% reduction in cross-sectional tumor size that was not documented twice. Median survival time was 6.5 months. This combination is not considered sufficiently active for further evaluation in this disease.

Therapy of advanced gastric carcinoma. The Georgetown-Lombardi Cancer Center experience.

Gastric carcinoma, despite a decreasing incidence in the United States over the past 40 years, is the seventh most common cause of cancer death in this country and remains a significant worldwide problem. The 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin (FAM) chemotherapy regimen, which was initially reported by Georgetown in 1979, has become a standard for advanced gastric carcinoma with response rates in the 40% range. The FAM regimen as well as subsequent trials conducted at Georgetown and our current approach to management of this tumor are discussed. Despite a decade of intensive clinical research, we have not identified a modification or innovation that is superior to the original FAM.

A study of oral etoposide, infusional cisplatin, and infusional 5-fluorouracil for locally advanced or metastatic non-small-cell lung cancer. A Mid-Atlantic Oncology Program study.

A combination of oral etoposide, infusional cisplatin (24-hr) and infusional 5-fluorouracil (5-day) was used to treat 87 patients with non-small-cell lung cancer in a Phase II trial. Twenty-six patients were Stage IIIB, and 61 patients were Stage IV (new international classification). The regimen was well tolerated, with 49% grade 3 or 4 toxicities of all types. Response rates, partial and complete, were 40%, (95% confidence interval: 30%, 51%) for Stage IV patients and 20% (95% confidence interval: 10%, 32%), in Stage IIIB. An additional 68% of patients in Stage IIIB and 45% of patients in Stage IV achieved stable disease and had a median survival of 8.8 months, similar to that of patients in partial remission. Median survival was 5.6 months (95% confidence interval: 4.4 months, 10.8 months) for Stage IV patients and 11.0 months (95% confidence interval: 8.8 months, 12.4 months), for Stage IIIB. Of interest was the finding of a higher response rate in patients with a shorter duration of symptoms (less than 6 months versus greater than 6 months).

The hydrolytic and transferase action of alternanase on oligosaccharides.

Alternanase is an enzyme which endo-hydrolytically cleaves the alpha-(1-->3), alpha-(1-->6)-linked D-glucan, alternan. The main products are isomaltose, alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-D-Glc and the cyclic tetrasaccharide cyclo[-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->]. It is also capable of acting on oligosaccharide substrates. The cyclic tetrasaccharide is slowly hydrolyzed to isomaltose. Panose and the trisaccharide alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-D-Glc both undergo transglycosylation reactions to give rise to the cyclic tetrasaccharide plus D-glucose, with panose being converted at a much faster rate. The tetrasaccharide alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->4)-D-Glc is hydrolyzed to D-glucose plus the trisaccharide alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-D-Glc. Alternanase does not act on isomaltotriose, theanderose (6(Glc)-O-alpha-D-Glcp sucrose), or alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->4)-alpha-D-Glc. The enzyme releases 4-nitrophenol from 4-nitrophenyl alpha-isomaltoside, but not from 4-nitrophenyl alpha-D-glucopyranoside, 4-nitrophenyl alpha-isomaltotrioside, or 4-nitrophenyl alpha-isomaltotetraoside.

A comparison of electromyography recorded parallel and transverse to the fibres of the anterior and posterior temporalis muscle in man.

Electrical activity recorded during voluntary clenching by platinum hook intra-cutaneous electrodes was significantly higher (p less than 0.01) when the electrodes were placed parallel to the muscle fibres than across the fibres. The correlation between the parallel and transverse EMG recordings was highly significant (p less than 0.001).

Gastrointestinal cancer in the elderly.

Gastrointestinal cancer is a commonly encountered problem in the elderly. Screening for colorectal cancer is cost effective and is increasingly important in this population because incidence rises rapidly in the seventh and eighth decades of life. Surgery remains by far the most important curative option and may be appropriate even at an advanced age. For patients who are not curable, quality of life is the yardstick by which palliative options should be evaluated.