Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Treatment patterns, outcomes, and resource utilization of patients with metastatic melanoma in the U.K.: the MELODY study.

BACKGROUND: Advanced melanoma is an aggressive disease with a poor prognosis. Approved therapy is limited in the U.K. and, until recently, no treatment had improved survival over best supportive care. A deeper understanding of current clinical practice will help new agents find a place in future treatment pathways. OBJECTIVES: To document U.K. clinical practice for the treatment of patients with unresectable stage III/IV (advanced) melanoma. METHODS: MELODY (melanoma treatment patterns and outcomes among patients with unresectable stage III/IV disease: a retrospective longitudinal survey) compiled registries of consecutive patients with malignant melanoma (any stage) between 1 July 2005 and 30 June 2006 from France, Italy and the U.K. Patients with advanced melanoma and ≥ 2 months of follow-up were eligible for analysis. RESULTS: There were 220 eligible patients identified in the U.K., of whom 117 (53.2%) received systemic therapy outside of clinical trials. Over half of these patients received dacarbazine as first- or second-line therapy. Healthcare-resource utilization was extensive and patients had short survival times: 1- and 2-year survival rates after first-line systemic treatment were 45.5% [95% confidence interval (CI) 37.1-53.6] and 24.7% (95% CI 17.7-32.3), respectively. CONCLUSIONS: Systemic and palliative treatments used to manage advanced melanoma in the U.K. are associated with considerable healthcare resource utilization and poor short-term survival.

Sunitinib in the management of gastrointestinal stromal tumours (GISTs).

AIMS: Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms of the gut with a 5-year survival of approximately 50%. Surgery remains the treatment of choice in resectable disease, with conventional chemotherapy largely ineffective. Over 90% of GIST possesses mutations in the c-KIT oncogene, producing an overactive tyrosine kinase, which may be driving the malignant process. Imatinib inhibits the aberrant tyrosine kinase and imatinib therapy in metastatic disease has shown significant clinical benefit. However, resistance typically develops within 2 years, with the need for further therapy. This article aims to introduce the reader to a new development in cancer therapeutics. METHODS: A literature search was performed using the MEDLINE database to identify publications relevant to the review. References within these articles were used to expand the search. Abstracts from recent ASCO symposia were hand searched for relevant articles. FINDINGS: Sunitinib (SU11248) is a novel multi-targeted tyrosine kinase inhibitor with activity not only against the receptor tyrosine kinase product of c-KIT but also other cell-signalling pathways that may be relevant in GIST; FLT3, platelet-derived growth receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). Two Phase II trials and one Phase III trial have investigated the activity of sunitinib against imatinib-resistant GIST. Early results showed significant benefits in time to disease progression that led to licensing of the drug in America and more recently in Europe. A Phase III trial comparing dose-increased imatinib and sunitinib in progressed GIST is currently planned. CONCLUSIONS: Initial clinical results with sunitinib are promising and suggest a future role. Further studies are needed before sunitinib can be recommended for the routine treatment of imatinib-refractory GIST.

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer.

Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine (Pounds 2132) and tegafur with uracil (Pounds 3385) were lower than costs for the intravenous Mayo regimen (Pounds 3593) and infusional regimens on the de Gramont (Pounds 6255) and Modified de Gramont (Pounds 3485) schedules over the same treatment period. Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens.

A phase I (tumour site-specific) study of carboplatin and temozolomide in patients with advanced melanoma.

Temozolomide is an oral alkylating agent that readily crosses the blood-brain barrier and has activity in patients with advanced melanoma. Carboplatin is a convenient outpatient treatment that also has activity in patients with melanoma. The purpose of this study was to assess the safety of a combination of temozolomide and carboplatin, and provide preliminary evidence of efficacy. In all, 30 patients were treated in two stages. In stage 1, patients received temozolomide 750 mg x m(-2), with escalating doses of carboplatin AUC 3-6. In stage 2, patients received temozolomide 1000 mg x m(-2), with increasing doses of carboplatin until dose-limiting toxicity (DLT) was experienced. In stage 1, 12 patients received 33 cycles of treatment. No grade 3/4 haematological toxicity was experienced up to carboplatin AUC 6. In stage 2, 18 patients received 55 cycles of treatment. The DLT was haematological with grade 4 myelosuppression seen with carboplatin AUC 5. In all, 11 patients were treated with carboplatin AUC 4 to gain further information on toxicity. Myelosuppression remained significant and common with grade 4 thrombocytopenia experienced in 50% of cycles. Two of 28 patients (7%) assessable for efficacy achieved a partial response. None of the 11 patients with brain metastases responded to treatment. The addition of carboplatin to temozolomide 1000 mg x m(-2) significantly adds to toxicity with frequent grade 3/4 myelosuppression. Preliminary information on efficacy demonstrates that it is unlikely that the combination can be given in doses sufficient to improve on the efficacy of temozolomide alone.

Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels.

PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125. PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to >or= twice its nadir level, confirmed by a second sample also >or= twice the nadir. RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression. CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials.

Diminished oesophageal traction forces with swallowing in gastro-oesophageal reflux disease and in functional dysphagia.

Relations between primary oesophageal peristaltic amplitude and traction force were studied in 30 normal volunteers, 12 patients with functional dysphagia, and 48 patients with gastro-oesophageal reflux disease, using a new intraluminal strain gauge device. Forces generated by swallowing in the normal oesophagus were 42 (35-60) g (median and interquartile range), a close positive correlation existing between traction force and contractile amplitude for each subject (r = 0.5 (0.38-0.6). Traction force increased with increasing balloon volume from 62 (50-73) g at 2 ml to 86 (70-105) g at 4 ml (p < 0.05), indicating distension related modulation of peristaltic force. Patients with oesophagitis generated lower traction forces on swallowing 30 (20-40) g compared with the normal subjects (p < 0.01), the degree of impairment being greatest in those patients with the most severe mucosal damage. Patients with gastro-oesophageal reflux without endoscopic oesophagitis also showed abnormal forces (32 22-38) g p < 0.01 v controls), which were similar to those patients with mild oesophagitis but were greater than those with severe oesophagitis (p < 0.05). In patients with functional dysphagia, forces were also impaired (28 (10-60) g p < 0.05 v controls) despite normal standard manometry. Our results show that measurement of the traction force generated by primary peristalsis provides information about oesophageal neuromuscular function that is not demonstrable by manometry alone and can be abnormal in patients with oesophageal symptoms in whom standard techniques are normal.

Identification of an abnormal esophageal clearance response to intraluminal distention in patients with esophagitis.

Esophageal clearance responses were studied by a new technique comprising a miniature electronic strain gauge attached to an inflatable balloon in 30 normal volunteers and 48 patients with gastroesophageal reflux disease. The pressure changes around the balloon and traction forces acting on the balloon were measured during graded balloon distention (0-12 mL of air for 30 seconds each inflation) in the lower and midesophagus. All normal volunteers responded to distention with development of swallow independent contractions above the balloon [65 mm Hg/30 s (range, 45-100 mm Hg/30 s)] together with generation of an aboral traction force [15 g (range, 9-20 g)]. Patients with reflux esophagitis showed a higher distention threshold for initiation of these responses, induced fewer proximal contractions [24 mm Hg/30 s (range, 0-38 mm Hg/30 s); P less than 0.01 vs. normal], and generated weaker traction forces [4 g (range, 0-6 g) at 10 mL P less than 0.01 vs. normal]. Patients with the most severe esophagitis showed greatest impairment of the clearance response (correlation = 0.7, P less than 0.01) and the greatest esophageal residence of refluxed acid (correlation = 0.5, P less than 0.01). These abnormalities appear to be of relevance to the pathophysiology of esophageal reflux disease although it remains to be determined whether they are the cause, or the result, of the esophagitis.

Oesophageal reflex responses: abnormalities of the enteric nervous system in patients with oesophageal symptoms.

An intraluminal balloon was used to study the peristaltic reflex, which is mediated by the intrinsic nerves of the oesophagus. Serial balloon distension was performed in nine asymptomatic volunteers and 133 patients with oesophageal symptoms. Eight of the volunteers had a normal response with proximal stimulation and distal inhibition of motility. Only 42 patients (31.6 per cent) had a normal response. The commonest abnormal response (39.1 per cent) was some form of failure of the distal inhibitory reflex. Other patterns of abnormality were an unresponsive oesophagus (15.8 per cent) with no motility change during balloon inflation, or spasm (13.5 per cent) proximal to the balloon. These alterations of secondary peristaltic activity suggest that there are abnormalities of the intrinsic (enteric) nerves of the oesophagus. Different abnormalities were found in patients with similar symptoms. Awareness of this difference might allow a more rational approach to treatment. This hypothesis was tested in a small pilot study treating functional dysphagia with cisapride. Three of nine patients had marked symptomatic improvement within 4 weeks and all three had an unresponsive oesophagus. The remaining six patients, who had failure of distal inhibition or a normal response, did not improve.

Recurrent reflux and wrap disruption after Nissen fundoplication: detection, incidence and timing.

One hundred and twenty-five patients with refractory gastro-oesophageal reflux disease underwent floppy Nissen fundoplication. Median follow-up was 52 months, and included endoscopy, manometry and prolonged pH recordings in all cases in addition to clinical assessment. Using objective criteria, 12 patients (9.6 per cent) developed recurrent reflux. In nine of these patients, endoscopy had suggested that the Nissen fundoplication had disrupted; wrap disruption was confirmed in seven patients who underwent reoperation. The median time to endoscopic recognition of wrap disruption was 7 months (range 3-10 months). In contrast, of 115 patients with endoscopic evidence of an intact fundoplication, only 3 (2.6 per cent) had recurrent reflux. Endoscopy allowed reliable differentiation between those with and without reflux control after operation (P less than 0.001). These results suggest that recurrent reflux after Nissen fundoplication is due to wrap disruption. This phenomenon occurs within the first postoperative year and can be recognized by informed endoscopic assessment.

Oesophageal manometry and pH recording does not predict the bad results of Nissen fundoplication.

A prospective study of the value of preoperative oesophageal manometry in selecting patients for gastro-oesophageal reflux surgery has been performed. One hundred and twenty-six consecutive patients had a floppy Nissen fundoplication with a median follow-up period of 48 months (range 21-96 months). Reflux was controlled in 116 patients (92.1 per cent). One hundred and five patients (83.3 per cent) had a clinically satisfactory result (Visick grades 1 and 2). Poor results were largely due to recurrent reflux, technical failure or the irritable bowel syndrome. An unsatisfactory result was not more likely in those with upright reflux, an oesophageal motility disorder or a competent cardia as defined by manometry. Preoperative oesophageal studies, other than those required to make an accurate diagnosis, were found to have no value in deciding the suitability of patients for surgical correction of gastro-oesophageal reflux.

Clinical implications of abnormal oesophageal motility.

The usefulness of oesophageal manometry as a clinical tool has been assessed in 202 patients requiring detailed investigation for troublesome oesophageal symptoms, who first presented between June 1979 and May 1982. Only 12 were found to have specific motility disorders such as achalasia and scleroderma. A total of 147 had a variety of non-specific motility disorders and, of these, 112 (76.2 per cent) had coexistent gastro-oesophageal reflux. There was a significant association between the symptoms of dysphagia and the occurrence of predominantly non-propagated motor activity in the oesophagus. A similarly significant relationship existed between crushing chest pain and oesophageal spasm. Despite this statistical association, detection and treatment of gastro-oesophageal reflux was found to be the most useful part of clinical management. Symptoms of associated motility disorders resolved in more than 90 per cent of patients treated by Nissen fundoplication. Preoperative assessment of motility was of no value in detecting those who might develop postoperative dysphagia. Oesophageal manometry is useful for the assessment of a small proportion of patients with oesophageal symptoms in whom gastro-oesophageal reflux has been excluded by vigorous investigation, including 24 h pH recording.

The lower oesophageal sphincter after floppy Nissen fundoplication.

The pressure and intra-abdominal length of the lower oesophageal sphincter (LOS) were measured by oesophageal manometry before and after floppy Nissen fundoplication (FNP) for intractable gastrooesophageal reflux. Control of reflux was assessed by 24 h pH recording and endoscopy. It was complete in 67 cases (84.8 per cent) in this non-consecutive series. In the group as a whole LOS pressure increased significantly after FNP, but the intra-abdominal length did not. LOS pressure decreased in 21 cases of whom 16 (76.2 per cent) still had perfect reflux control. Likewise, intra-abdominal length decreased in 41 cases of whom 36 (87.8 per cent) had good reflux control. There was no evidence of a compensatory increase in length to account for reflux control when LOS pressure decreased. When a length-pressure diagram was plotted for the postoperative measurements no clear separation of those with persistent reflux could be seen. These results suggest that the measured changes in LOS pressure and length following FNP are an artefact of surgery rather than the means by which the operation controls gastro-oesophageal reflux.

Scintigraphic assessment of oesophageal motility: what does it show and how reliable is it?

Computer analysed transit of a liquid bolus containing Tc99m (RT) was compared with manometry for the detection of oesophageal motility disorders in 151 patients with a variety of oesophageal symptoms. Manometry was abnormal in 99 of whom 44 had abnormal RT (sensitivity 44%); it was normal in 52 of whom 37 had normal RT (specificity 71%). The commonest manometric abnormalities were non-specific motility disorders characterised by abnormalities of peristaltic amplitude, waveform or baseline. Radionuclide transit was abnormal in only 32/77 (42%) of these. Achalasia, which is characterised by complete aperistalsis, was the least common diagnosis, but all five cases had abnormal RT. Simultaneous manometry and RT in 30 patients showed that the transit of a liquid bolus through the oesophagus is determined by the propagation rather than the form of the peristaltic contraction. Because non-specific motility disorders are common in clinical practice, RT is not a useful screening test for oesophageal dysmotility.