Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial.

BACKGROUND: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. METHODS: SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893. FINDINGS: Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). INTERPRETATION: Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF. FUNDING: Cancer Research UK (CR UK/98/001) and Pharmacia.

Socioeconomic differences impact overall survival in advanced ovarian cancer (AOC) prior to achievement of standard therapy.

PURPOSE: Survival difference between socioeconomic groups with ovarian cancer has persisted in the United Kingdom despite efforts to reduce disparities in care. Our aim was to delineate critical episodes in the patient journey, where deprivation has most impact on survival. METHODS: A retrospective review of 834 patients with advanced ovarian cancer (AOC) between 16/8/07-16/2/17 at a large cancer centre serving one of the most deprived areas of the UK. Using the Index of Multiple Deprivation (IMD), patients were categorised into five groups. RESULTS: Surgery was more common in less deprived patients (p < 0.00001). Across IMD groups, there were no differences in complete (R0) cytoreduction rate (r = 0.18, p > 0.05), age, or comorbidity. The R0/total cohort rate increased with increasing IMD group (p < 0.0001). Patients refusing any intervention belonged exclusively to the three most deprived groups; 5/7 patients who refused surgery belonged to the most deprived IMD group. Overall survival in the total patient group was less in IMD group 1-2 compared to 9-10 (p = 0.002). On multivariate analysis, IMD group was not an independent predictor of survival (p > 0.05). CONCLUSIONS: Socioeconomic differences in survival manifest in patients not receiving surgical treatment for AOC and are not purely explained by comorbidity, age, stage, or histological factors.

Outcomes Following Interval Debulking Surgery in Primary Peritoneal Carcinoma.

AIM: Primary peritoneal carcinoma (PPC) has a poor prognosis, with a median survival of 11-24 months. Unlike ovarian cancer, there exist no published data on the effectiveness of interval debulking surgery (IDS) in PPC and it is not routine practice. Our series compared outcomes in patients with PPC treated with IDS following chemotherapy versus patients treated with chemotherapy alone. PATIENTS AND METHODS: A retrospective case-note analysis was undertaken of all patients diagnosed with PPC in the Pan-Birmingham network between May 2000 and October 2008. Data were analysed for age, performance status, response to chemotherapy, surgical outcomes, subsequent treatments, site of relapse, median progression-free (PFS) and overall (OS) survival. Analysis for PFS and OS was undertaken using both Kaplan-Meier and log-rank analysis. RESULTS: A total of 44 patients with histologically-proven PPC were identified: 41 patients received chemotherapy with platinum combination or alone; 17/44 (39%) of patients underwent IDS following chemotherapy and 15 of these had optimal debulking; 3/15 (20%) had a complete pathological response. The recurrence rate for the surgical group was 11/17 (65%) including those with suboptimal debulking, whereas disease recurred in 25/27(93%) of the non-surgical group. The median PFS was 25 months (range=8-33 months) in the IDS group compared to 9 months (range=0-30 months) in the non-surgical group (p=0.001). The median OS was 48 months in the IDS group compared to 18 months in the non-surgical group (p=0.0016). The median OS for the whole patient cohort was 32 months. CONCLUSION: The median OS for the whole cohort compares favourably with previously published survival data of 11-24 months. IDS in selected cases of PPC appears to improve median OS and PFS in PPC and we would recommend that surgery is considered as a treatment option in all patients who have a good response to chemotherapy or entry into a clinical trial.

Survival and Toxicity Following Chemoradiation for Carcinoma of the Cervix - Impact of Multiple-phase Treatment and Shielding.

AIM: We report on outcomes and significant grade 3-4 late toxicities between January 1999 and October 2006 following introduction of multi-phase treatment and effect of shielding in treatment of cervical cancer with concurrent chemoradiation. PATIENTS AND METHODS: Radiotherapy dose by phase, recurrence, survival and toxicity data was collated by a retrospective review of clinical notes. Shielding information was retrieved from original planning films. RESULTS: 3-year survival for stages I, II and III disease were 89%,76% and 51% respectively. Local pelvic failure was 9%. Overall significant late toxicity (SLT) rate was 13%, with lower rates for post-operative treatment than primary chemoradiation (4% vs. 16%). SLT with single phase treatment was 29% versus 12% following multiphase EBRT and 16% when <2 areas were shielded versus 6% with ≥3 shielded areas (p=0.01). CONCLUSION: Shielding and multi-phase treatment not only reduce dose to organs at-risk but can also reduce late toxicity without compromising local control or survival.

Chemotherapy for Uterine Carcinosarcoma with Carboplatin, Ifosfamide and Mesna.

BACKGROUND/AIM: Uterine carcinosarcomas (UCSs) are highly aggressive, rare, biphasic tumors composed of epithelial and mesenchymal elements. Surgery remains the mainstay of treatment in early-stage disease. Adjuvant pelvic radiotherapy improves locoregional control without proven overall survival (OS) benefit. Although adjuvant ifosfamide-based combination chemotherapy with cisplatin or paclitaxel has shown superiority to radiotherapy or single-agent chemotherapy in randomized controlled trials, there is no consensus on a standard regimen due to toxicities. The aim of this retrospective study was to assess the efficacy and toxicity of a novel combination chemotherapy using carboplatin, ifosfamide and mesna (CIM) and compare with other regimens for patients with UCSs in both the adjuvant and palliative setting. PATIENTS AND METHODS: Between 1997 and 2010, 60 patients with UCS, 70% of whom with international federation of gynecology and obstetrics (FIGO) stage III/IV disease, were treated with adjuvant or palliative chemotherapy. Two groups were identified: Group1 (n=22) included patients receiving CIM chemotherapy; and group 2 (n=38) receiving other regimens (carboplatin/paclitaxel/cisplatin/doxorubicin/epirubicin). RESULTS: After a median follow-up of 60 months, disease in seven patients in group 1 (CIM) and 20 patients in group 2 had progressed/relapsed. Out of these, six patients in group 1 and 13 patients in group 2 had died. The progression-free survival (PFS) and OS for patients treated with adjuvant or palliative CIM was 35 months [95% confidence interval (CI) =0.26-0.43] and 47 months (95% CI=0.38-0.56; log-rank, p=0.001) respectively, whereas for group 2 patients treated with other regimens, PFS was 27.48 months (95% CI=0.20-0.33) and OS was 30 months (95% CI=0.21-0.38; log-rank, p=0.001). While none of the patients in group 1 experienced neurotoxicity or other grade 3 or 4 toxicities, 3/38 patients in group 2 experienced grade 3 neutropenia, 4/38 had peripheral sensory neuropathy, 6/38 patients had treatment deferred due to toxicities or allergic reaction to paclitaxel. CONCLUSION: In the phase III randomized controlled trial combination of ifosfamide and taxanes has shown PFS and OS benefit when compared to single-agent ifosfamide at the expense of significant toxicities. Results from our study show that the combination of CIM is an effective and safe alternative regimen for patients with advanced UCSs. In addition to improved OS and PFS, the main advantage of this regimen over taxane-based regimens includes minimal neuropathy, less use of steroids, and low risk of allergic reaction. CIM should be considered in future prospective studies looking at the treatment of UCS.

Chemotherapy for advanced endometrial cancer with carboplatin and epirubicin.

UNLABELLED: Endometrial cancer is the most common gynecological cancer in the Western world. In early-stage disease, surgery remains the mainstay of treatment. Adjuvant pelvic radiotherapy reduces the risk of pelvic recurrence, however, without improvement in overall survival. The aim of the present study was to assess the efficacy and toxicity of carboplatin and epirubicin combination chemotherapy for patients with advanced and high-risk endometrial cancer. PATIENTS AND METHODS: Between 1999 and 2007, 43 patients with endometrial cancer were treated with carboplatin and epirubicin. Two groups were identified: Group 1 (n=34) included patients with stage III endometrial cancer receiving adjuvant chemotherapy; and group 2 included those with metastatic endometrial cancer (n=9). RESULTS: After a median follow-up of 37 months, disease in 19 patients had progressed/relapsed (12 patients from group 1; 7 from group 2) and 23 patients had died (15 from group 1; 8 from group 2). The median time-to-progression was 62 months and median overall survival was 64 months. The median survival for patients in group 1 was 69 months and for those in group 2 was 22 months. Ten patients (27.9%) experienced grade 3 or 4 toxicities. There were no cases of treatment-related cardiac failure or neuropathy. CONCLUSION: Cisplatin, carboplatin, anthracyclines and taxanes are the most active agents in endometrial cancer. Combination chemotherapy leads to better progression-free survival and overall survival, however, this is at the expense of increased toxicity. RESULTS from our study show that the combination of carboplatin and epirubicin is an effective alternative regimen for patients with advanced endometrial cancer. In addition, treatment-related toxicity is minimal when compared to anthracyclines and platinum agents. There is a particular advantage of this regimen over taxane-based regimens, including minimal neuropathy, less use of steroids and low risk of allergic reaction and alopecia.

Reversible branch retinal artery occlusion following intravenous cisplatin chemotherapy for cervical carcinoma.

Cisplatin (CDDP) is a chemotherapeutic agent widely used to treat solid tumours. We present a case of reversible CDDP-associated branch retinal artery occlusion.

Fatal Clostridium difficile infection associated with vinorelbine chemotherapy: case report and literature review.

Differentiating between chemotherapy-related diarrhoea and Clostridium difficile-associated diarrhoea (CDAD) can be extremely difficult. There is increasing evidence that CDAD can be seen in patients on chemotherapy without prior antibiotic usage. We report the first case of CDAD secondary to vinorelbine chemotherapy and review the literature.

Chemotherapy related encephalopathy in a patient with Stage IV cervical carcinoma treated with cisplatin and 5-fluorouracil: a case report.

INTRODUCTION: Chemotherapy related encephalopathy is commonly reported with certain forms of chemotherapy but few reports note an association with low dose 5-Fluorouracil. CASE PRESENTATION: A 57-year-old Caucasian lady received her first cycle of Cisplatin and 5-Fluorouracil for palliative treatment of cervical carcinoma, and presented several days later with signs of encephalopathy. Several causes were eliminated, and encephalopathy related to 5-Fluorouracil was thought to be the most likely cause. Magnetic Resonance Imaging of the head revealed changes related to the chemotherapy received. Symptoms resolved completely within three days of presentation. CONCLUSION: Encephalopathy from low dose 5-Fluorouracil is not well documented in the literature. Fluid rehydration and supportive treatment is required. Signs and symptoms resolved completely with no residual effects on follow up.

Primary squamous cell carcinoma of the breast: achieving long-term control with cisplatin-based chemotherapy.

Pure primary squamous cell carcinoma (SCC) of the breast is rare and difficult to treat. Published series suggest a poor response to conventional breast chemotherapy. A 66-year-old woman with locally advanced SCC of the breast received combined-modality treatment with high-dose radiation therapy (59 Gy in 22 fractions); mastectomy; and chemotherapy with cisplatin 50 mg/m(2), mitomycin-C 6 mg/m(2), and ifosfamide 3 g/m(2) given in 21-day cycles. She remained disease free for 10 years from presentation and died from an unrelated cause. We would suggest that this case lends support to the use of high-dose radiation therapy and platinum-based chemotherapy in the management of this difficult condition.

Prolonged trastuzumab therapy in a patient with recurrent breast cancer and anthracycline-induced cardiac failure.

Current practice precludes patients with pre-existing cardiac dysfunction from trastuzumab therapy. A 57-year-old patient with HER2 positive metastatic breast cancer and anthracycline-induced cardiac failure was safely treated with trastuzumab. At 46 months, left ventricular ejection fraction (LVEF) did fall to 38.3%, but 8 months later has recovered to 47%. She remains disease free and asymptomatic from cardiac dysfunction more than 6 years following breast cancer recurrence. We review the evidence for the use of trastuzumab in patients with controlled cardiac dysfunction, and suggest this group of patients should be considered for treatment with trastuzumab if no other or only less efficacious therapeutic options are available.

Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom.

PURPOSE: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. EXPERIMENTAL DESIGN: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. RESULTS: No increase in clinically significant late toxicity was seen in the mutation carriers. CONCLUSIONS: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

Acute chemotherapy-related toxicity is not increased in BRCA1 and BRCA2 mutation carriers treated for breast cancer in the United Kingdom.

PURPOSE: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003. EXPERIMENTAL DESIGN: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers. RESULTS: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02). CONCLUSIONS: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.

Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer. METHODS: In NEAT, we compared four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) with six cycles of CMF alone. In the BR9601 trial, we compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. The primary end points were relapse-free and overall survival. The secondary end points were adverse effects, dose intensity, and quality of life. RESULTS: The two trials included 2391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P<0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P<0.001) and death from any cause (0.67; 95% CI, 0.55 to 0.82; P<0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P=0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life. CONCLUSIONS: Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer. (ClinicalTrials.gov number, NCT00003577 [ClinicalTrials.gov].).

Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas.

BACKGROUND: The role of prophylactic antibacterial agents after chemotherapy remains controversial. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance. RESULTS: A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections. CONCLUSIONS: Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization.