Immediate and delayed autologous abdominal microvascular flap breast reconstruction in patients receiving adjuvant, neoadjuvant or no radiotherapy: a meta-analysis of clinical and quality-of-life outcomes.

BACKGROUND: Effects of postmastectomy radiotherapy (PMRT) on autologous breast reconstruction (BRR) are controversial regarding surgical complications, cosmetic appearance and quality of life (QOL). This systematic review evaluated these outcomes after abdominal free flap reconstruction in patients undergoing postoperative adjuvant radiotherapy (PMRT), preoperative radiotherapy (neoadjuvant radiotherapy) and no radiotherapy, aiming to establish evidence-based optimal timings for radiotherapy and BRR to guide contemporary management. METHODS: The study was registered on PROSPERO (CRD42017077945). Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index and ClinicalTrials.gov were searched (January 2000 to August 2018). Study quality and risk of bias were assessed using GRADE and Cochrane's ROBINS-I respectively. RESULTS: Some 12 studies were identified, involving 1756 patients (350 PMRT, 683 no radiotherapy and 723 neoadjuvant radiotherapy), with a mean follow-up of 27·1 (range 12·0-54·0) months for those having PMRT, 16·8 (1·0-50·3) months for neoadjuvant radiotherapy, and 18·3 (1·0-48·7) months for no radiotherapy. Three prospective and nine retrospective cohorts were included. There were no randomized studies. Five comparative radiotherapy studies evaluated PMRT and four assessed neoadjuvant radiotherapy. Studies were of low quality, with moderate to serious risk of bias. Severe complications were similar between the groups: PMRT versus no radiotherapy (92 versus 141 patients respectively; odds ratio (OR) 2·35, 95 per cent c.i. 0·63 to 8·81, P = 0·200); neoadjuvant radiotherapy versus no radiotherapy (180 versus 392 patients; OR 1·24, 0·76 to 2·04, P = 0·390); and combined PMRT plus neoadjuvant radiotherapy versus no radiotherapy (272 versus 453 patients; OR 1·38, 0·83 to 2·32, P = 0·220). QOL and cosmetic studies used inconsistent methodologies. CONCLUSION: Evidence is conflicting and study quality was poor, limiting recommendations for the timing of autologous BRR and radiotherapy. The impact of PMRT and neoadjuvant radiotherapy appeared to be similar.

ANTECEDENTES: En pacientes sometidas a una reconstrucción mamaria (breast reconstruction, BRR) con tejido autólogo se discuten los efectos de la radioterapia post-mastectomía (post-mastectomy radiotherapy, PMRT) en las complicaciones quirúrgicas, el resultado estético y la calidad de vida (quality of life, QOL). Esta revisión sistemática evaluó dichos resultados tras una reconstrucción mamaria con un colgajo libre abdominal en pacientes tratadas con PMRT, radioterapia preoperatoria (Neo RT) y sin radioterapia (RT), a fin de establecer los momentos óptimos de la RT y BRR basados en la evidencia, como guía del tratamiento actual. MÉTODOS: El estudio se registró en la base de datos PROSPERO (CRD42017077945). Se realizaron búsquedas en Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index y Clinicaltrials.gov (enero de 2000-agosto de 2018). La calidad de los estudios y el riesgo de sesgo se evaluaron mediante las herramientas GRADE y ROBINS-I de la Cochrane, respectivamente. RESULTADOS: Se identificaron 12 estudios que incluían 1.756 pacientes (350 PMRT, 683 sin RT y 723 Neo RT), con una mediana de seguimiento de 27,1 meses (rango 12,0-54,0) para PMRT, 16,8 meses (1,0-50,3) para Neo RT y 18,3 meses (1,0-48,7) para sin RT. Se incluyeron tres cohortes prospectivas y nueve retrospectivas. No hubo estudios aleatorizados. Los estudios comparativos de RT evaluaron la PMRT (n = 5) y la Neo RT (n = 4). Todos los estudios fueron de baja calidad, con riesgos de sesgo de moderados a graves. Las complicaciones graves fueron similares entre los grupos: PMRT (n = 92) versus sin RT (n = 141), razón de oportunidades (odds ratio, OR) 2,35, i.c. del 95% 0,63-8,81), P = 0,200; Neo RT (n = 180) versus no RT (n = 392) (OR 1,24, i.c. del 95% 0,76-2,04), P = 0,390; o RT combinada (PMRT y neoadyuvante) (n = 272) versus no RT (n = 453) (OR 1,38, i.c. del 95% 0,83-2,32), P = 0,220. Los estudios de calidad de vida y de resultados estéticos utilizaron metodologías poco consistentes. CONCLUSIÓN: La evidencia es contradictoria y la calidad de los estudios muy pobre, hechos que limitan las posibles recomendaciones para el momento de la BRR con tejido autólogo y la RT. El impacto de la PMRT o la Neo RT parecen ser similares.

Dose-finding study of weekly docetaxel, epirubicin and capecitabine, as first-line treatment in advanced breast cancer.

BACKGROUND: Combinations of anthracycline, taxane and fluoropyrimidine are highly active in advanced breast cancer (ABC). In a phase II study of epirubicin 50 mg/m(2), docetaxel 75 mg/m(2), and infusional 5-FU 200 mg/m(2)/day, we found dose-limiting neutropenia and frequent central venous catheter complications. An alternative approach has been tested using weekly fractionation of docetaxel, and oral capecitabine. METHODS: Initially, six women with ABC were treated with epirubicin 60 mg/m(2) day 1, docetaxel 25 mg/m(2) days 1,8,15, and capecitabine 1,000 mg/m(2) twice daily days 1-14, every 21 days. Six further patients received the above with capecitabine escalated to 1,500 mg/m(2) RESULTS: Four DLTs occurred in six patients at the second dose level (febrile neutropenia in 2). There were frequent dose delays/reductions, and fatigue, nausea/vomiting, and diarrhoea were common. Overall, six of ten assessable patients achieved a partial response. CONCLUSIONS: An active regimen, but significant haematological toxicity precluded dose further escalation.

Aromatase inhibitors and musculoskeletal symptoms.

AIMS: Recent evidence shows aromatase inhibitors (AIs) to be of benefit over tamoxifen in the adjuvant setting. It is also apparent that musculoskeletal symptoms associated with AIs may be a significant problem in the clinical setting. The aim of this article is to review the data on AIs with respect to musculoskeletal symptoms in the adjuvant setting. MATERIAL AND METHODS: A review on the literature relating to AIs in the adjuvant setting and musculoskeletal symptoms. RESULTS: Results of phase III trials show lower incidence of musculoskeletal symptoms than reported in the clinical setting. DISCUSSION: AIs offer a significant advantage over tamoxifen. More research is required to ascertain the cause and to define the spectrum of musculoskeletal symptoms reported in women taking AIs. Decision of appropriate treatment should be made jointly between clinician and patient after full discussion of the risks and benefits.

A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer.

AIMS: Whole-breast radiotherapy (WBRT) after conservative surgery for early breast cancer is a routine standard of care. Despite this, a number of uncertainties in management still exist. Over recent years, a number of new technologies have allowed the development of partial-breast irradiation, with the intention of improving the risk-benefit relationship of routine breast radiotherapy. We report the results of a trial comparing partial- with WBRT, with prolonged follow-up. MATERIALS AND METHODS: Between 1986 and 1990, 174 women were randomised to receive conventional whole-breast radiotherapy (WBRT) (40 Gy in 15 fractions), with a tumour-bed boost or partial-breast irradiation by a variety of techniques. Recruitment was problematic, and the trial closed prematurely well before meeting its recruitment target. RESULTS: A trend was observed towards higher local recurrence and a higher locoregional recurrence rate after irradiation of the tumour bed alone. Distant recurrence and survival were the same. CONCLUSIONS: Conclusions are limited in view of the failure to complete accrual of the target of 400 participants, and in the context of the techniques of partial-breast radiotherapy used during this study, which would not compare with those in current use. Tumour-bed irradiation alone cannot currently be recommended as routine treatment outside the context of clinical trial.

Morbidity of tamoxifen-perceptions of patients and healthcare professionals.

There is little published data comparing patients' and doctors' perceptions of tamoxifen-related morbidity and toxicity, in particular in terms of side-effects which are not medically serious but which disrupt quality of life. We undertook a questionnaire-based study of 210 randomly selected, disease-free pre- and post-menopausal breast cancer patients to assess perceived morbidity whilst taking tamoxifen. We also questioned 143 healthcare professionals, including nurses, GPs and oncologists, on their opinions of tamoxifen-related side-effects. This study suggests that patients experience significant morbidity while taking adjuvant tamoxifen but will tolerate this for the sake of anticipated benefits. Healthcare professionals particularly hospital-based doctors and specialist nurses tend to overestimate the prevalence and severity of tamoxifen-associated symptoms.

Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis.

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.

Optimum anthracycline-based chemotherapy for early breast cancer.

Adjuvant chemotherapy improves the overall survival of women treated after surgery for early breast cancer. Several trials have suggested that anthracycline-containing regimens are more effective than those that do not contain anthracyclines. A modest overall benefit has also been confirmed by the Early Breast Cancer Trialists' Collaborative Group overview. Newer agents, such as the taxanes, are now being tested in the adjuvant setting in randomised trials. The control group of such studies should receive the optimum standard treatment. There are several anthracycline-based regimens in common use, varying in terms of the type of anthracycline used, the dose, and drug scheduling. We review the available evidence and consider whether the optimum anthracycline-containing chemotherapy schedule has now been identified.

A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with advanced breast cancer.

BACKGROUND: This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability. PATIENTS AND METHODS: Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted 'blind' of the randomized drug treatment. RESULTS: Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%, respectively, P = 0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events. CONCLUSIONS: Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.

Survival from cancer: local control and radiotherapy.

Adjuvant radiotherapy is considered to be highly effective in maintaining local control but is widely perceived to confer no survival advantage in the management of solid tumours. However, recent adjuvant radiotherapy studies are beginning to show survival improvements in parallel with improvements in loco-regional disease control.

A randomised comparison of oestrogen suppression with anastrozole and formestane in postmenopausal patients with advanced breast cancer.

The relative efficacy and tolerability of the aromatase inhibitors anastrozole (Arimidex) and formestane are assessed in a direct comparative trial in postmenopausal women with advanced breast cancer. Final results are available and reported here only for oestradiol suppression. Patients were randomised to receive either oral anastrozole, 1 mg once daily, or formestane, 250 mg every 2 weeks intramuscularly. In the anastrozole group, mean serum oestradiol levels fell from 32.1 pmol/l at baseline to 6.5 pmol/l at week 1, and similar levels of suppression were maintained over the next 3 weeks. In the formestane group, mean serum oestradiol levels fell from 31.0 pmol/l at baseline to 9.5 pmol/l at the week 1 assessment. In this group, serum oestradiol levels tended to rise by the 2- and 4-week measurements, i.e. immediately before the next injection was due. Based on the 2- and 4-week measurements, the mean falls in oestradiol levels were 79 and 58% in the anastrozole and formestane groups, respectively (p = 0.0001). More effective and consistent suppression of oestradiol was achieved with anastrozole at the therapeutic dose of 1 mg once daily, orally, than with formestane at the standard dose of 250 mg every 2 weeks, intramuscularly.

An audit of the management of malignant hypercalcaemia.

A protocol was designed to help junior doctors to manage patients with malignant hypercalcaemia (MH). Seventy-five patients received 30 mg, 60 mg or 90 mg doses of pamidronate, depending on their initial serum calcium level. Fifty-four (72%) patients achieved normocalcaemia (NC) within 5 days after a single infusion of pamidronate. A further ten (13%) patients reached NC after a second dose, and 11 (15%) remained hypercalcaemic until death. NC was maintained for a median duration of 24 days. Patients received, on average, 30 mg less pamidronate than that given in the manufacturer's dosing schedule. The protocol was considered effective, economical and practical in the routine management of MH.

Etoposide-related myocardial infarction.

The occurrence of a myocardial infarction is reported after chemotherapy containing etoposide, in a man with no risk factors for coronary heart disease. Possible causal mechanisms are discussed.

Skin telangiectasia: the influence of radiation dose delivery parameters in the conservative management of early breast cancer.

A retrospective analysis was performed to study the occurrence of skin telangiectasia in patients with conservatively treated early breast cancer who were given postoperative radiotherapy that included an electron boost. Patients managed in two different centres were treated with identical techniques but different schedules of radiotherapy. Electron boost site telangiectasia was less common in those patients treated at the centre that employed higher doses, longer schedules and lower fraction sizes of both photons and electrons. These results require prospective confirmation but they suggest that schedules of radiotherapy employing lower fraction sizes, longer treatment times and higher total doses may minimize the incidence of skin telangiectasia.

Malignant schwannoma following treatment for Hodgkin's disease.

Two cases of malignant schwannoma are reported 13 and 15 years following combined modality treatment for Hodgkin's disease. Both patients survived for only 15 months. The aetiology of this rare condition is discussed.

High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer.

UNLABELLED: Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100 mg m-2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 5 1/2 months and the median survival was 18 1/2 months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 days) and mean time to absolute neutrophil count recovery (ANC > 1,000 x 10(6) litre) from the start of treatment was 11 days. Moderate to severe epithelial toxicity (WHO grade 3 or 4) accompanied 43% of courses and was dose limiting. CONCLUSION: High dose, dose intensive chemotherapy has an excellent initial therapeutic effect in advanced breast cancer but does not prolong duration of remission or overall survival beyond that of standard treatment. Although subcutaneous rG-CSF curtailed the expected duration of neutropenia substantially, the overall incidence of neutropenia and of infections requiring intravenous antibiotics was high. Furthermore, almost half of the courses were complicated by moderate to severe oral mucositis and/or mild to moderate palmar and plantar inflammation. The lack of survival benefit and excess toxicity seriously limits the wider application of this regime. It should not be used in place of standard dose palliative chemotherapy for metastatic breast cancer.