Medical Oncology Workload in Europe: One Continent, Several Worlds.

AIMS: The workload pressure on medical oncologists will increase in the near future. There are no comprehensive data available about the current workload of medical oncologists in Europe. Here we report the European results of a global survey of the workload of medical oncologists. MATERIALS AND METHODS: An online survey was distributed through a snowball method via national oncology societies to chemotherapy-prescribing physicians in 21 European countries. We compared the workload of medical oncologists in Eastern European countries (EECs) and Western European countries (WECs). The primary measure of workload was the annual number of new cancer patient consults seen per oncologist. RESULTS: In total, 495 oncologists from 16 European countries completed our survey: 100 from seven EECs and 395 from nine WECs. The median number of annual consults per medical oncologist was 225 in EECs compared with 175 in WECs (P < 0.001). The proportion of medical oncologists seeing more than 300 consults/year was 35% (35/100) in EECs compared with 18% (68/395) in WECs. The median number of patients seen in a full day clinic was 25 in EECs and 15 in WECs (P < 0.001). Eastern European medical oncologists reported spending a median of 25 min per new consultation compared with 45 min in WECs (P < 0.001). The top two reported barriers in both EECs and WECs to patient care were high clinical volumes and insufficient time for reading. CONCLUSION: The clinical workload of medical oncologists in EECs was substantially higher than in WECs. European health policymakers and educators need to address existing disparities in the workload of medical oncologist, undertake plans for future workforce supply and consider alternative models of care.

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04).

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. PATIENTS AND METHODS: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. RESULTS: With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS  = 0.94, 95%CI = 0.84-1.06, p = 0.340; HRIDFS  = 0.91, 95%CI = 0.82-1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS  = 0.82, 95%CI = 0.67-1.00; HRIDFS  = 0.78, 95%CI = 0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS  = 0.75, 95%CI = 0.58-0.97) and OS HROS  = 0.69, 95%CI = 0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS  = 0.76, 95%CI = 0.63-0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. CONCLUSIONS: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

A randomized phase III study of 72 h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3).

BACKGROUND: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary toxicity often necessitates drug cessation and death occurs in 1%-2% of patients. A continuous infusion of bleomycin might reduce lung toxicity when compared with the conventional weekly boluses given as part of standard BEP chemotherapy. PATIENTS AND METHODS: A phase 3 trial was conducted based on 212 men with IGCCCG good prognosis metastatic germ cell tumours with 1 : 1 randomization. They were stratified for age, smoking history and renal function. Patients received either conventional BEP with weekly bleomycin (30 000 units/week i.v. bolus) or as a 90 000 unit infusion on day 1 over 72 h. The primary endpoint was CT assessed lung toxicity, secondary endpoints included progression-free survival (PFS), changes in lung function testing and quality of life. Repeated measures mixed effects model was used to analyse the data. RESULTS: CT assessed lung toxicity for the infusional and conventional arm patients were respectively 80% versus 62% at the end of treatment and 54% versus 51% at 1-year post-treatment. There was no significant difference between the two arms for CT assessed lung toxicity (estimated regression coefficient = 1.4, 95% CI: -0.36, 3.16). Older patients had higher toxicity (coefficient = 4.81, 95% CI: 3.04, 6.58). Lung toxicity increased after 1 cycle and peaked at end of treatment (P ≤ 0.002) and then declined. Lung function testing did not predict for subsequent lung damage. The median follow-up was 2.5 years. Two-year PFS rate (infusional: 93%, conventional: 94%; hazard ratio =0.91, 95% CI: 0.33, 2.52) was similar. Cough (P = 0.002) but not shortness of breath (P ≥ 0.09) was associated with bleomycin toxicity. CONCLUSIONS: Infusional bleomycin has no advantage over standard administration. It supports abandoning routine pulmonary function testing, instead the presence of cough should be sought and the early use of CT scanning of the chest to evaluate potential lung toxicity is preferred.

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour.

BACKGROUND: We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability. METHODS: Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP. RESULTS: Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72-1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1-6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64-100%). CONCLUSION: Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

Vinorelbine and infusional 5-fluorouracil in anthracycline and taxane pre-treated metastatic breast cancer.

AIMS: To evaluate the efficacy and toxicity of a combination of intravenous vinorelbine and 5-fluorouracil (5-FU) given by continuous infusion in the treatment of metastatic breast cancer previously treated with anthracyclines and taxanes. MATERIALS AND METHODS: Sixty-one patients with metastatic breast cancer were treated with intravenous vinorelbine 30 mg/m2 on days 1 and 8 of each 21-day cycle together with 5-FU 200 mg/m2/day by continuous infusion. All had previously been treated with an anthracycline and 41% had also been previously treated with a taxane. All had normal haematological, renal and hepatic function and all but three had an Eastern Cooperative Oncology Group performance score of 2 or better. RESULTS: The overall response rate by World Health Organization criteria was 46% (28 patients); excluding nine non-evaluable patients gave a response rate of 54%. In patients who had previously been treated with both an anthracycline and a taxane, a response rate of 50% was observed (12 of 24 patients). Severe toxicity was uncommon, as was toxicity attributable to infusional 5-FU. Myelosuppression was rarely severe, but was common and led to delay or dose reduction in 38% of treatments. Eleven patients (18%) were admitted with fever and/or neutropenia and one patient died. The median received dose intensity was vinorelbine 16 mg/m2/week and 5-FU 143 mg/m2/day. CONCLUSIONS: The combination of vinorelbine and infusional 5-FU is active in metastatic breast cancer, including in patients previously treated with an anthracycline and a taxane. Toxicity is generally manageable, but myelosuppression is significant at this dose regimen. Recommended doses for routine clinical use are 5-FU 200 mg/m2/day and intravenous vinorelbine 30 mg/m2 days 1 and 15 on a 28-day cycle.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG).

Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception.

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Impartial long-term review of vertical banded gastroplasty in a low volume community hospital practice.

BACKGROUND: There is some concern whether bariatric surgery can be done well at low volumes or in a community hospital setting. This paper reports an impartial assessment of 25 vertical banded gastroplasties (VBG) over 13 years in a 228-bed non-teaching community hospital. METHODS: Charts were reviewed and patients interviewed by an independent investigator. Complications, weight loss, satisfaction and quality of life were assessed. RESULTS: There were no fatalities, no splenic tears, no stomal stenosis and no symptomatic gastroesophageal reflux. Two reoperations and five incisional hernias were noted. Hypertension was eliminated in 57% and dyspnea in 55%. BMI fell from 44.3 to 34.9 kg/m2 after 6.2 years. BMI decreased more than 10 kg/m2 (10-30) for 15 patients and less than 10 kg/m2 for 10 patients (4-10 for 7, 0 for 1 and a gain for 2). 56% of patients were fully satisfied with the results. Quality of life indicated excellent physical function, physical role and lack of body pain, good general health, social function, emotional role and mental health, but lower vitality. 100% felt better than a year ago. CONCLUSION: Results from a low-volume community hospital general surgical practice are similar to those from specialized series. Obesity is so common, its non-surgical treatment so ineffective and the VBG so well established, that excluding this intervention from community hospitals is untenable.

A simple technique for laparoscopic vertical banded gastroplasty--the JOVO procedure.

A simple technique for laparoscopic vertical banded gastroplasty is described. With the surgeon to the patient's left, four trochars are placed as cephalad as possible. Short gastric vessels are divided and the posterior wall of the stomach mobilized. The ETS-Flex with Articulating Head (Ethicon Endosurgery Inc.) is used to divide the stomach close to a 42-french bougie against the lesser curvature. An additional stapler bite abuts directly against a 28-french bougie to obtain correct stoma size. A ribbon of Prolene mesh is pulled through a tunnel behind the stomach at the apex of the divided gastroplasty and sutured around the distal end of the gastroplasty. To date we have used this method successfully in 5 patients with 1-11 months of follow-up. Although we lack a sufficient number of patients or follow-up for definitive conclusions, we believe this technique will produce good results, as it reproduces exactly that used successfully in open surgery and our early results parallel those following open surgery.

Technique and early results of outpatient laparoscopic mesh onlay repair of ventral hernias.

BACKGROUND: This report describes the technique and early results of a simple outpatient laparoscopic ventral hernia repair. METHODS: Data were gathered prospectively for all laparoscopic ventral hernia repairs from January 1996 to December 1997 at a 228-bed hospital. Prolene mesh was stapled to the peritoneal surface of the abdominal wall, leaving sac in situ and mesh uncovered. Patients were seen by the operating surgeon within 2 months, and by an impartial surgeon (J.S.) after 3 to 14 months (average, 7 months; median, 6 months). RESULTS: Repairs involved 44 hernias with orifice sizes 2 to 20 cm in diameter, and an average area of 20 cm(2). Of these 44 hernias, 36 were postoperative and 8 primary. Furthermore, 20% were recurrent hernias. There were four conversions. The outpatient rate was 98%, with one readmission for ileus. The early recurrence rate was 5%. CONCLUSIONS: Laparoscopic mesh onlay repair is a safe, easy, and effective procedure with minimal discomfort and a low early recurrence rate that can be performed safely on an outpatient basis.

Factors contributing to laparoscopic failure during the learning curve for laparoscopic Nissen fundoplication in a community hospital.

This study was done to determine the factors contributing to laparoscopic failure (conversion to open surgery or early reoperation) during the learning curve for laparoscopic Nissen fundoplication in a 228-bed nonteaching community hospital. Data were gathered prospectively for the first 100 consecutive patients booked for elective laparoscopic Nissen fundoplication by the four general surgeons at the hospital. All complications were recorded contemporaneously, and particular note was taken of the factors surrounding conversion to open surgery and reoperation within 100 days of surgery. There were no deaths. The conversion rate was 20% and the early reoperation rate 6%. There were two late recurrences. The average operative time was 117 minutes and the average length of stay 1.8 days; 37 operations were performed on outpatients. The laparoscopic failure rate was 26% (18/68) during a surgeon's first 20 operations and 11% (3/28) thereafter (P < 0.09); the corresponding conversion rates were 22% and 4% (P < 0.05). During a surgeon's first 20 operations, the laparoscopic failure rate rose from 21% (12/57) to 55% (6/11) (P < 0.04) if a second surgeon did not assist. After 20 operations, this difference lost its significance. Intrathoracic herniation of the stomach was found preoperatively in 11 (44%) of 25 operations followed by laparoscopic failure and (8%) 6 of 75 without (P < 0.0002). Laparoscopic failure had no correlation with patient age, sex, ASA classification, duration of symptoms, or referring physician's specialty. The individual learning curve for laparoscopic Nissen fundoplication requires about 20 operations to surmount. Factors leading to laparoscopic failure during the learning curve are the surgeon's inexperience, absence of experienced help, and the presence of intrathoracic herniation.

Validation of computer-assisted manufacture of titanium plates for cranioplasty.

We have constructed 300 titanium cranioplasty plates, over 150 cases using a computerised technique, the remainder by external impression. The clinical follow-up of these cases over 8 years has shown consistently good results that justify our simple low-cost method of manufacturing these plates. Both techniques require the provision of a model on which to construct the plate. In the traditional technique, an approximate model is derived from the resected bone or a direct impression of the defect over the patient's scalp. Using the computerised technique, a more accurate model of the defect and the surrounding bone is milled in polyurethane foam from cross-sectional computerised tomographic (CT) scans. Sheet titanium is pressed to shape from a design outlined on a counterdie. The subsequent stages of the plate construction are then the same for both methods. This study describes the stages of the model manufacture, the validation of its accuracy and the plate construction that follows. Use of the computerised method has resulted in a reduction of errors, enabling the manufacture of a smaller plate than was possible previously. It has also enabled design changes through the achievement of greater accuracy in fit.

Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial.

We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37-55%) with ECF, and 21% (95% CI, 13-28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8-20%) for the ECF arm, and 5% (95% CI, 2-10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting.

The effect of diazepam and promethazine treatment during pregnancy on the somatic development of human offspring.

The postnatal longitudinal somatic, neurological, mental, and behavioral developments were studied in children at birth, 8, 15, and 24 months of life, whose mothers were treated during pregnancy with clinical doses of diazepam (n = 126) and promethazine (n = 127) and whose mothers were unexposed. The latter group was differentiated in negative (n = 256) and positive (n = 102) control children. The positive control group involved mothers who had pregnancy complications similar to those of mothers in the drug groups but who were not treated with CNS-active drugs during pregnancy. It is very difficult to recruit persons for the study and control groups who are appropriate for comparative evaluation. Only firstborns and the so-called "normal" newborn infants were studied; children with low birth weight, major abnormalities, severe neonatal diseases, etc., were excluded. In this article the study design, study materials, and somatic (weight, length, head circumference) development are described. At birth, children had a lower weight in the diazepam group, but it was not noted at the eighth month of postnatal life.

Rectal carcinoma metastatic to the breast.

We report the first case in our experience of metastasis to the breast from a previous rectal carcinoma. Metastases to the breast are rare in themselves; for them to occur secondary to a previous rectal carcinoma makes this unusual.

A prospective study of computer-aided design and manufacture of titanium plate for cranioplasty and its clinical outcome.

The use of computerized three dimensional imaging and automated milling of models to produce accurate titanium plates for the reconstruction of craniofacial defects is described. A total of 148 patients have had extensive calvarial defects repaired using this (computer aided design and manufacture) technique developed in our unit. Of these, 141 were repaired secondarily (delayed cranioplasty), whilst seven were repaired immediately following craniectomy (single stage cranioplasty). All cases were assessed for accuracy of fit, restoration of natural skull contour and aesthetics. Seventy-two patients were reviewed after 1 year to determine the effect on adverse preoperative symptoms. Of the plates 97% had an excellent or good intraoperative fit. The modal insertion time was only 15 minutes. Postoperatively 98% resulted in the restoration of natural skull shape and symmetry. After 1 year, 82% of patients had complete resolution or diminution in severity of the adverse symptoms. A staphylococcus infection necessitated the temporary removal of one plate.