Survival analysis part IV: further concepts and methods in survival analysis.
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Clinical Trials as Topic↗
Biomedical subjects
S B Love
Publications and source records attributed to S B Love.
Survival analysis Part III: multivariate data analysis -- choosing a model and assessing its adequacy and fit.
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Clinical Trials as Topic↗
Survival analysis part II: multivariate data analysis--an introduction to concepts and methods.
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Clinical Trials as Topic↗
Survival analysis part I: basic concepts and first analyses.
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Clinical Trials as Topic↗
Learning the hard way! Setting up an RCT of aromatherapy massage for patients with advanced cancer.
Aromatherapy massage is used in cancer palliative care to improve quality of life but there is little evidence for its effectiveness. A large pragmatic multicentre randomized controlled trial was set up to examine the effectiveness of aromatherapy in improving psychological distress and quality of life in patients with cancer. This paper examines the challenges encountered in the design and execution of the study. The original design, i) focused on palliative care patients with advanced disease; ii) had both a no-intervention and a treatment control group (relaxation therapy); and iii) adopted 90% power for sample size calculations. A varied measurement strategy was employed. Recruitment proved difficult, referrers were 'gate-keeping', patients were often too ill to approach and others declined. The trial was modified to ensure viability. Eligibility was extended to all patients with cancer irrespective of stage, the relaxation group was removed and the power reduced to 80%. Although it is not generally good practice to change a study design once recruitment has started, the changes were consistent with the original basic study aims and design principles. The data collection phase was successfully completed in July 2002.
Aromatherapy↗
Identification of objective pathological prognostic determinants and models of prognosis in Dukes' B colon cancer.
BACKGROUND AND AIMS: There is a need for objective easily determined pathological prognostic parameters in Dukes' B colon carcinoma to allow selection of such patients for further treatment as the role of adjuvant chemotherapy for these patients remains unclear. This study was initiated to assess the influence of pathological factors on prognosis in an unselected prospective series of Dukes' B colonic cancer. METHODS: The Gloucester Colorectal Cancer study, established in 1988, recruited more than 1000 cases. Meticulous pathological assessment of the 268 Dukes' B colonic cancer resections in this series included evaluation of all pathological factors that could influence staging and prognosis. All patients entered a comprehensive follow up system. RESULTS: Four pathologically determined factors--peritoneal involvement, venous spread (both submucosal and extramural), spread to involve a surgical margin, and perforation through the tumour-were independent prognostic factors in multivariate analysis. Combining these four factors into a simple cumulative scoring system generated clinically useful prognostic groups. CONCLUSIONS: The cumulative prognostic index allows apportionment of patients with Dukes' B colon cancer into defined prognostic groups, which in turn could allow more objective selection of patients for adjuvant therapy, especially as part of clinical trials.
Adult↗
A randomized controlled trial to evaluate the role of interferon as initial and maintenance therapy in patients with follicular lymphoma.
The purpose of this study was to evaluate the role of interferon as initial and maintenance therapy in patients with newly diagnosed follicular lymphoma. Between 1984 and 1994, 204 patients with newly diagnosed Stage III or Stage IV follicular lymphoma were randomized to receive either, Chlorambucil (CB): 10 mg daily for 6 weeks, followed by a 2-week interval, with 3 subsequent 2-week treatment periods at the same dose, separated by 2-week intervals, or, CB given concurrently with interferon (IFN). IFN was given at a dose of 3 x 10(6)units thrice weekly, subcutaneously, throughout the 18-week treatment period. Responding patients were subsequently randomized to receive maintenance IFN at the dose and schedule described above, or to expectant management. The overall response rate was 161/204 (78%), complete remission being achieved in 24% of patients. Neither the addition of IFN to the initial treatment, nor the use of maintenance IFN influenced response rate, remission duration or survival. This study was undertaken to determine whether IFN, given in combination with, and then subsequent to, CB would alter the clinical course of patients with follicular lymphoma. Disappointingly, this objective was not achieved, no advantage having been demonstrated for the addition of IFN.
Adult↗
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.
Analysis of Variance↗
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.
Aged↗
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.
Adult↗
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.
Adult↗
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.
Disease Progression↗
Properties of HPV-positive and HPV-negative anal carcinomas.
Evidence of human papillomavirus (HPV) can be found in up to 85 per cent of anal carcinomas. In the vulva, a discrete subset of HPV-positive carcinomas which show koilocytic morphology and distinct clinical features has recently been identified (warty carcinoma). The morphological and prognostic features of HPV-positive and HPV-negative anal carcinomas were compared in this study of the tumour distribution of HPV DNA. Vulval and anal neoplasia are similar in many ways and we have also looked to see if their similarity extends to 'warty' morphology in relation to HPV status. Thirty-five resection specimens of anal carcinoma were examined with biotin-labelled probes for HPV 6, 11, 16, and 18 DNA, using a non-isotopic in situ hybridization (ISH) technique. No tumour was found to contain HPV 6, 11, or 18. Twenty-four (72 per cent) showed positivity for HPV 16 DNA. Staining was homogeneous and independent of local squamous, basaloid, or ductal differentiation. The majority of tumours showed staining suggestive of episomal, non-productive HPV infection. HPV-positive tumours were more likely to occur in the anal canal than perianally and to show a mixed squamous and basaloid appearance. No difference between the two groups was found in patient age, presence of adjacent dysplasia, ductal differentiation, or prognosis. There was no correlation between condylomatous tumour morphology and HPV 16 DNA positivity; thus, a subset equivalent to vulval warty carcinoma could not be identified.
Anus Neoplasms↗
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.
Adult↗
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.
Analysis of Variance↗
Myeloma during a decade: clinical experience in a single centre.
One hundred and fifty-six patients with multiple myeloma were treated over a period of 12 years at St. Bartholomew's Hospital. The progress of the disease was affected in 96/156 patients (61%). Response was defined as achieving a plateau of M component. A partial or complete response was seen in 68/120 patients treated conventionally (56.5%), and in 28/36 patients treated with high-dose therapy (77.7%). The median survival of the group as a whole was 20 months, with a 2-year survival of just over 40%. In the 36 patients treated with high-dose therapy, median survival was 6 years, and in a small group who have had maintenance Interferon therapy, the median has not yet been reached. In a univariate analysis, age, intensity of therapy, haemoglobin and creatinine levels were significant, but multivariate analysis showed that only age and intensity of therapy were independent predictors for survival. The outlook for relapsed patients who showed progression of disease remains poor, but palliation was best achieved by steroid and Interferon in combination. Patients who achieve complete responses and are maintained on Interferon appear to be doing better both in terms of freedom from symptoms and in survival, and methods to enable an elderly population to tolerate this form of therapy need to be explored.
Adult↗
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.
Adult↗
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.
Aged↗