Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.

BACKGROUND: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial. PATIENTS AND METHODS: Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). RESULTS: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. CONCLUSION: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

e-Consent in UK academic-led clinical trials: current practice, challenges and the need for more evidence.

BACKGROUND: During the COVID-19 pandemic, in-person healthcare visits were reduced. Consequently, trial teams needed to consider implementing remote methods for conducting clinical trials, including e-Consent. Although some clinical trials may have implemented e-Consent prior to the pandemic, anecdotes of uptake for this method increased within academic-led trials. When the increased use of this process emerged, representatives from several large academic clinical trial groups within the UK collaborated to discuss ways in which trialists can learn from one another when implementing e-Consent. METHODS: A survey of UKCRC-registered Clinical Trials Units (CTUs) was undertaken in April-June 2021 to understand the implementation of and their views on the use of e-Consent and experiences from the perspectives of systems programmers and quality assurance staff on the use of e-Consent. CTUs not using e-Consent were asked to provide any reasons/barriers (including no suitable trials) and any plans for implementing it in the future. Two events for trialists and patient and public involvement (PPI) representatives were then held to disseminate findings, foster discussion, share experiences and aid in the identification of areas that the academic CTU community felt required more research. RESULTS: Thirty-four (64%) of 53 CTUs responded to the survey, with good geographical representation across the UK. Twenty-one (62%) of the responding CTUs had implemented e-Consent in at least one of their trials, across different types of trials, including CTIMPs (Clinical Trial of Investigational Medicinal Product), ATIMPs (Advanced Therapy Medicinal Products) and non-CTIMPs. One hundred ninety-seven participants attended the two workshops for wide-ranging discussions. CONCLUSION: e-Consent is increasingly used in academic-led trials, yet uncertainties remain amongst trialists, patients and members of the public. Uncertainties include a lack of formal, practical guidance and a lack of evidence to demonstrate optimal or appropriate methods to use. We strongly encourage trialists to continue to share their own experiences of the implementation of e-Consent.

Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

Mastectomy or conservation for early breast cancer: psychological morbidity.

A consecutive series of 197 women under 70 years of age with operable breast cancer, randomised to treatment by a conservation technique in comparison to mastectomy, were assessed using structured interviews. The prevalence of cases of anxiety and depression was high before treatment commenced, there were fewer cases in the conservation group but no significant difference at 3 or 12 months in the number of new cases, social adjustment, or capacity to return to work. Attitudes to treatment showed significant differences between the groups, more women in the conservation group were able to wear their usual clothes and most women rated the cosmetic result highly. Patients were more likely to stop sexual intercourse completely after mastectomy. An effective conservation technique should be an attractive treatment choice available to selected women with early breast cancer.

Transforming growth factor-beta isoform expression in human ovarian tumours.

The expression patterns of members of the transforming growth factor-beta (TGF-beta) family were analysed in 96 primary ovarian tumours by RNAse protection assay. mRNA for the three mammalian isoforms, TGF-beta 1, TGF-beta 2 and TGF-beta 3, was detected in 46, 66 and 66% of 74 malignant tumours, respectively, with the predominant patterns of expression being either dual or triple co-expression. TGF-beta II receptor expression, detected by reverse-transcription PCR, was present in 92% malignant tumours. Expression patterns were similar between malignant, borderline and benign tumours, although TGF-beta 1 incidence was reduced in benign tumours. In malignant tumours, the incidence of TGF-beta 1 expression was less than that of either TGF-beta 2 (P = 0.02) or TGF-beta 3 (P = 0.0014), while in both malignant and borderline tumours, TGF-beta 2 and TGF-beta 3 tended to be co-expressed. Aneuploid tumours were more likely than diploid tumours to express multiple rather than single forms of TGF-beta (P = 0.018). The incidence of TGF-beta 1 expression was reduced in PR-moderate/rich (PR > 20 fmol/mg protein) relative to PR-negative/poor tumours (P = 0.048), while TGF-beta 3 expression was increased in ER-moderate/rich (ER > 20 fmol/mg protein) tumours compared to ER-negative/poor tumours (P = 0.0012). Expression of TGF-beta 3, but not TGF-beta 1 or TGF-beta 2, was associated with advanced stage disease (P = 0.014) and, in the malignant group, reduced survival (P = 0.02) with a hazard ratio of 2.6. These data suggest a possible role for TGF-beta 3 in the progression of ovarian cancer.

Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome.

Patients with extensive ulcerative colitis are entered into surveillance programs that aim to detect premalignant changes. Biopsy specimens have been collected in the St Mark's Hospital (London) surveillance program over a 22-year-period. Specimens from patients reported as having dysplasia were reexamined. A total of 207 biopsy specimens from 86 patients were graded by five experienced pathologists according to the severity of the dysplasia. The overall agreement between the pathologists grading the specimens was poor; each pair agreed on between 42% and 65% of the slides. The best agreement was for slides that were said to show no dysplasia. Comparison with clinical outcome indicated that the pathologists most likely to diagnose dysplasia in patients with carcinoma were also likely to diagnose dysplasia in patients who did not go on to develop carcinoma. Calculating an average grade of dysplasia did not significantly improve diagnostic accuracy. Despite the findings of this interobserver study, dysplasia has been a successful marker in clinical practice. Pathologists should ensure that they have access to previous slides from the same patient and adequate clinical information before reporting biopsies as positive for dysplasia. An additional biopsy should usually be undertaken before surgery is considered.

Basis of sialic acid heterogeneity in ulcerative colitis.

To test the suggestion that an inherited defect in colonic mucus rendering it susceptible to degradation by bacterial enzymes may be an important factor in the aetiology of ulcerative colitis, 650 colonoscopic and rectal biopsy specimens from 166 patients with colitis were stained by mild periodic acid Schiff (mPAS), which shows sialic acid that is deficient in O-acetyl substituents. There was an excess of mPAS positive sialic acid in patients with chronic ulcerative colitis, but the increased expression was patchy and coincided with a morphological change in the form of epithelial hyperplasia (metaplasia). Hyperplasia was more common in the rectum and in women and was associated with, and presumably secondary to, active inflammation. It is concluded that variation in the structure of sialic acid is acquired and is therefore unlikely to be implicated in the aetiology of ulcerative colitis.

Influence of local peritoneal involvement on pelvic recurrence and prognosis in rectal cancer.

AIMS: To evaluate the influence of involvement of the peritoneal surface by carcinoma of the rectum on local recurrence and prognosis. METHODS: Prospective analysis of pathological prognostic factors in 209 resections for rectal carcinoma between 1988 and 1993 with meticulous pathological technique particularly to assess the relation of tumour to the peritoneal surface. Comprehensive clinical follow up with cause of death established from all available sources of information (hospital and general practitioner data) with necropsies where necessary. Local recurrence was determined by accepted clinical, radiological and pathological criteria. RESULTS: Local peritoneal involvement was detected in 25.8% (54/209) of cases. It was more common in women and was associated with tumour differentiation, size and site, and lymph node involvement. Local peritoneal involvement showed considerable prognostic disadvantage in all cases and in curative cases alone. Multivariate analysis demonstrated independent prognostic disadvantage for all cases although this was lost in the curative group. With a 30 month median follow up time, comprehensive clinical surveillance detected 25 (12.0%) local recurrences. Thirteen (52%) palliative cases had shown spread to involve the mesorectal (deep, circumferential) resection margin. Of the 12 curative cases, six were upper rectal cancers with local peritoneal involvement suggesting that tumour seeding into the pelvic peritoneal cavity was the cause of local recurrence. Local recurrence of the six other rectal tumours was probably because of intraluminal seeding in two, involvement of the distal margin in one, extensive extramural venous involvement in two, and tumour spread to the bladder in one. CONCLUSIONS: Comprehensive pathological analysis of a resection specimen can identify cases with a high probability of local recurrence which may benefit from early adjuvant therapy. Involvement of the peritoneal surface is a common event in rectal cancer, has adverse prognostic influence and may be an important factor in local recurrence of upper rectal carcinoma.

Clinical importance of DNA content in rectal cancer measured by flow cytometry.

The DNA content of 369 rectal cancers was measured by flow cytometry. One hundred and four (28%) were diploid, 252 (68%) were aneuploid, and 13 (3.5%) were tetraploid. Diploid cancers were associated with an improved 5 year survival (p less than 0.001) and were more likely to present at an early stage. DNA content, however, did not confer independent prognostic information in a Cox model based on four discrete pathological variables. Patients were classified by a new system of prognostic grouping and those with a very good or a very poor outlook were removed leaving 137 prognostic group III patients. No further substratification of this group by DNA content or by four additional pathological variables could be achieved. As the new prognostic system is not improved by the addition of ploidy, routine adoption of flow cytometry in the assessment of rectal cancer cannot be recommended.

Population based randomized study of uptake and yield of screening by flexible sigmoidoscopy compared with screening by faecal occult blood testing.

OBJECTIVES: To compare the feasibility of mass screening by flexible sigmoidoscopy with screening by faecal occult blood testing (Haemoccult) and both tests combined. DESIGN: Patients were randomised to screening by flexible sigmoidoscopy, faecal blood testing, or both tests. The flexible sigmoidoscopy examinations were performed by a general practitioner. SETTING: General practice. SUBJECTS: 3744 patients aged 50-75 years. MAIN OUTCOME MEASURES: Uptake, positive results, detection of neoplasia, complications, and recall for diagnostic colonoscopy. RESULTS: Uptake was significantly higher in the flexible sigmoidoscopy group (46.6%) than in the faecal blood test group (31.6%; P<0.001) or than in the group having both tests (30.1%; P<0.001). Telephone reminders increased uptake of sigmoidoscopy to 61.8%. In total, 1116 sigmoidoscopy examinations were performed without major complication. Polyps were found in 19. 3% (95% confidence interval 17.0% to 21.6%) but only 6.8% (5.3% to 8. 3%) had adenomas and 2.4% (1.5% to 3.3%) "high risk" adenomas. Cancer was detected in four subjects. The faecal blood test yielded positive results in 0.8% (0.2% to 1.4%) but missed at least one cancer and 30 cases of adenoma which were found by sigmoidoscopy in the combined group. Use of histological criteria-shown elsewhere to correlate with future risk of colorectal cancer-to select "positive" patients could reduce recall for diagnostic colonoscopy from about 20% to less than 5%. CONCLUSIONS: Some of the predicted obstacles to screening with flexible sigmoidoscopy are surmountable. Clear evidence relating to efficacy will be obtained only from a randomised controlled trial.

Prognostic value of direct spread in Dukes' C cases of rectal cancer.

Seventy-six cancers with involved lymph nodes but with limitation of direct spread in continuity to the bowel wall (Astler-Coller C1 cases) were matched with Astler-Coller C2 cases for clinical variables, macroscopic appearance of tumor, grade of differentiation, and number of positive lymph nodes. Despite this stringent matching, spread was shown to be an important prognostic variable in univariate survival analysis. Estimated five-year survival for Astler-Coller C1 cases was just below 80 percent, equivalent to B2 (Dukes' B) cases. When spread was analyzed in the presence of additional prognostic variables (character of invasive margin and lymphocytic infiltration) by multivariate modeling, its independent prognostic status was maintained. Improved survival for C1 cases was not explained by a lower incidence of local pelvic recurrence. Mechanisms to account for the better prognosis are proposed. This study reaffirms the importance of multivariate techniques of analysis in the assessment of prognosis of patients with rectal cancer.

A new prognostic classification of rectal cancer.

Only 60% of patients having radical surgery for rectal cancer are cured of their disease. The ideal system of classification would identify just two categories--the cured and those who will die of their disease. Specimens from 379 patients who had undergone radical surgery for rectal cancer more than 20 years ago were re-examined in order to identify discrete pathological variables that independently influence long-term survival. The selected variables were given weighted scores and the score range was divided to provide four prognostic groups. The model was tested on a second data set comprising 331 patients and gave similar results. The new prognostic classification is simple to use and is superior to staging by the method of Dukes because it places twice as many patients into groups that provide a confident prediction of clinical outcome.

The prognostic importance of peritoneal involvement in colonic cancer: a prospective evaluation.

BACKGROUND & AIMS: Prognostic parameters specific to the colon have been somewhat neglected compared with the rectum. This study was instituted to assess the influence of local peritoneal involvement (LPI) on pelvic and intraperitoneal recurrence and prognosis in an unselected, prospective series of colonic cancer resections. METHODS: Meticulous examination of 412 resections included evaluation of the relation of the tumor to the peritoneal surface. Histological assessment was as follows: 1, peritoneal involvement absent (81 resections, 20%); 2, inflammatory reaction with tumor close but not present at the surface (89 resections, 22%); 3, peritoneal surface unequivocally infiltrated (112 resections, 27%); and 4, peritoneal involvement with ulceration and tumor cells lying apparently free in the peritoneum (130 resections, 32%). RESULTS: LPI showed strong independent prognostic influence in both curative surgery groups and in all patients. In multivariate analysis in curative surgery, LPI was the most powerful prognostic indicator. It was significantly associated with palliative surgery, extent of local spread, and mucinous subtype and predicted cases with subsequent intraperitoneal recurrence and/or persistence. CONCLUSIONS: LPI is a common event in colonic cancer and is a consistent predictor of subsequent intraperitoneal recurrence. It is an important independent pathological prognostic parameter and may supersede other parameters in current usage in colonic cancer prognosis.

Review of survival analyses published in cancer journals.

Survival analysis has found widespread applications in medicine in the last 10-15 years. However, there has been no published review of the use and presentation of survival analyses. We have carried out a systematic review of the research papers published between October and December 1991 in five clinical oncology journals. A total of 132 papers were reviewed. We looked at several aspects of study design, data handling, analysis and presentation of the results. We found that almost half of the papers did not give any summary of length of follow-up; that in 62% of papers at least one end point was not clearly defined; and that both logrank and multivariate analyses were frequently reported at most only as P-values [63/84 (75%) and 22/47 (47%) respectively]. Furthermore, although many studies were small, uncertainty of the estimates was rarely indicated [in 13/84 (15%) logrank and 16/47 (34%) multivariate results]. The procedure for categorisation of continuous variables in logrank analyses was explained in only 8/49 (16%) papers. The quality of graphs was felt to be poor in 43/117 (37%) papers which included at least one survival curve. To address some of the presentational inadequacies found in this review we include new suggested guidelines for the presentation of survival analyses in medical journals. These would complement the statistical guidelines recommended by several clinical oncology journals.

What do cancer patients mean when they complain of concentration and memory problems?

Cognitive function items are increasingly included in quality of life measures, and complaints of concentration and memory difficulties are often reported by cancer patients. The aim of this study was to examine the factors influencing patients' level of complaint by comparing subjective reports with objective test performance of a sample of adult lymphoma patients, disease-free and > or = 6 months after treatment. There was no significant difference between complainers and non-complainers in sociodemographic or clinical characteristics or in their performance on standard neuropsychometric tests of concentration and memory. Those reporting concentration and memory difficulties had significantly higher scores on measures of anxiety, depression and fatigue. This calls into question the validity of including cognitive function items in self-report quality of life measures. Patients who report concentration and memory difficulties should be screened for clinically significant and potentially remediable mood disorder. Objective testing remains the method of choice for assessing higher mental function.

Influence of delay on survival in patients with breast cancer: a systematic review.

BACKGROUND: Most patients with breast cancer are detected after symptoms occur rather than through screening. The impact on survival of delays between the onset of symptoms and the start of treatment is controversial and cannot be studied in randomised controlled trials. We did a systematic review of observational studies (worldwide) of duration of symptoms and survival. METHODS: We identified 87 studies (101,954 patients) with direct data linking delay (including delay by patients) and survival. We classified studies for analysis by type of data in the original reports: category I studies had actual 5-year survival data (38 studies, 53,912 patients); category II used actuarial or multivariate analyses (21 studies, 25,102 patients); and category III was all other types of data (28 studies, 22,940 patients). We tested the main hypothesis that longer delays would be associated with lower survival, and a secondary hypothesis that longer delays were associated with more advanced stage, which would account for lower survival. FINDINGS: In category I studies, patients with delays of 3 months or more had 12% lower 5-year survival than those with shorter delays (odds ratio for death 1.47 [95% CI 1.42-1.53]) and those with delays of 3-6 months had 7% lower survival than those with shorter delays (1.24 [1.17-1.30]). In category II, 13 of 14 studies with unrestricted samples showed a significant adverse relation between longer delays and survival, whereas four of five studies of only patients with operable disease showed no significant relation. In category III, all three studies with unrestricted samples supported the primary hypothesis. The 13 informative studies showed that longer delays were associated with more advanced stage. In studies that controlled for stage, longer delay was not associated with shorter survival when the effect of stage on survival was taken into account. INTERPRETATION: Delays of 3-6 months are associated with lower survival. These effects cannot be accounted for by lead-time bias. Efforts should be made to keep delays by patients and providers to a minimum.

Who and what influences delayed presentation in breast cancer?

This study aimed to examine the extent and determinants of patient and general practitioner delay in the presentation of breast cancer. One hundred and eighty-five cancer patients attending a breast unit were interviewed 2 months after diagnosis. The main outcome measures were patient delay in presentation to the general practitioner and non-referral by the general practitioner to hospital after the patient's first visit. Nineteen per cent of patients delayed > or = 12 weeks. Patient delay was related to clinical tumour size > or = 4 cm (P = 0.0002) and with a higher incidence of locally advanced and metastatic disease (P = 0.01). A number of factors predicted patient delay: initial breast symptom(s) that did not include a lump (OR 4.5, P = 0.003), not disclosing discovery of the breast symptom immediately to someone else (OR 6.0, P < 0.001), seeking help only after being prompted by others (OR 4.4, P = 0.007) and presenting to the general practitioner with a non-breast problem (OR 3.5, P = 0.03). Eighty-three per cent of patients were referred to hospital directly after their first general practitioner visit. Presenting to the GP with a breast symptom that did not include a lump independently predicted general practitioner delay (OR 3.6, P = 0.002). In view of the increasing evidence that delay adversely affects survival, a large multicentre study is now warranted to confirm these findings that may have implications for public and medical education.

Prognostic factors in anal squamous carcinoma: a multivariate analysis of clinical, pathological and flow cytometric parameters in 235 cases.

Clinical, pathological and flow cytometric parameters have been analysed by univariate and multivariate analysis to define those parameters of important prognostic influence in 235 cases of surgically treated squamous carcinoma of the anus and perianal skin. Patients had been treated by anorectal excision (166 patients) or by local excision (69). Analyses were carried out on five data sets--the two surgical subgroups, two groups distinguished by site of tumour and on all 235 patients. Univariate analysis showed many parameters to be of prognostic influence, although histological typing of tumours into the more common histological subtypes was of no prognostic value. Parameters of independent prognostic significance in multivariate analysis were those indicating depth of spread, inguinal lymph node involvement and DNA-ploidy. In this study the subdivision of the rarer types of anal canal tumour, such as mucoepidermoid carcinoma, microcystic squamous carcinoma and small cell anaplastic carcinoma, was relevant confirming that these tumours have a poor prognosis. It is now felt that surgery should not be employed as primary treatment in most cases of anal cancer and the results of this study have to be interpreted with caution when applied to patients treated with radiotherapy with or without chemotherapy. Nevertheless, our findings suggest that the most useful prognostic information can be gleaned from accurate clinical staging and an assessment of DNA-ploidy status.