A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.

BACKGROUND: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. OBJECTIVE: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. DESIGN: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). SETTING: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. PARTICIPANTS: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l. MAIN OUTCOME MEASURES: Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. RESULTS: Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy. LIMITATIONS: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. CONCLUSIONS: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.

Use of Tumor Markers in Gastrointestinal Cancers: Surgeon Perceptions and Cost-Benefit Trade-Off Analysis.

BACKGROUND: Gastrointestinal cancers constitute the third most common cancers worldwide. Tumor markers have long since been used in the postoperative surveillance of these malignancies; however, the true value in clinical practice remains undetermined. OBJECTIVE: This study aimed to evaluate the clinical utility of three tumor markers in colorectal and esophagogastric cancer. METHODS: A systematic review of the literature was undertaken to elicit the sensitivity, specificity, statistical heterogeneity and ability to predict recurrence and metastases for carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 and CA125. European surgeons were surveyed to assess their current practice and the characteristics of tumor markers they most valued. Data from the included studies and survey were combined in a cost-benefit trade-off analysis to assess which tumor markers are of most use in clinical practice. RESULTS: Diagnostic sensitivity and specificity were ranked the most desirable characteristics of a tumor marker by those surveyed. Overall, 156 studies were included to inform the cost-benefit trade-off. The cost-benefit trade-off showed that CEA outperformed both CA19-9 and CA125, with lower financial cost and a higher sensitivity, and diagnostic accuracy for metastases at presentation (area under the curve [AUC] 0.70 vs. 0.61 vs. 0.46), as well as similar diagnostic accuracy for recurrence (AUC 0.46 vs. 0.48). CONCLUSIONS: Cost-benefit trade-off analysis identified CEA to be the best performing tumor marker. Further studies should seek to evaluate new tumor markers, with investigation tailored to factors that meet the requirements of practicing clinicians.

The impact of local guidelines on the tumour marker requesting patterns of a General Surgery Department.

BACKGROUND: The inappropriate use of tumour markers (TMs) is a common problem. The aim of this audit was to evaluate the impact of local guidelines on the TM requesting patterns of a General Surgery Department. METHODS: CA 125, CA 19-9, CA15-3, CEA, AFP and HCG requests from all hospital surgical locations were audited over two periods of eight months before and after the implementation of local requesting guidelines. RESULTS: Postintervention, total TM requests decreased by 32% while patient requests decreased by 9.8%. Single TM requesting increased and requests for panels containing four or more TMs decreased from 279 to 60 requests (78% reduction). CONCLUSION: Interdepartmental collaboration and the implementation of local guidelines have resulted in a change in requesting behaviour, most notably a reduction in multiple TM panel requests.

An audit of tumour marker utilization in Greece.

INTRODUCTION: Several international organizations have published guidelines for the correct use of tumour markers in clinical practice. However, there are reports that clinicians do not adhere to these guidelines in clinical practice. The present study constitutes an audit of TM use in a major hospital in Northern Greece. Purpose of our study is to quantify the magnitude of inappropriate TM requests as well as the corresponding financial cost. METHODS: We examined retrospectively all TM requests between 10/2006 and 07/2007 in the department of biochemistry of our hospital. The tumour markers included in our study were: CA 19-9, CA 125, CA 15-3, AFP, NSE, CYFRA 21-1 and CEA. RESULTS: We found 9782 inappropriate TM orders. For five of them - namely CA 125, AFP, CA 19-9, CYFRA 21-1 and NSE - the proper requests were below 10%. There were 5.6 TM requests per patient. The total cost for inappropriate TM reached 239,748 euro, which corresponds to a monthly cost of 23,974euro. CONCLUSIONS: There is considerable inappropriateness in the utilization of TM in Greece which corresponds to significant financial cost. Various measures should be applied in order to increase the cost-effectiveness of TM use.

A cost-effectiveness approach to the Norwegian follow-up programme in colorectal cancer.

BACKGROUND: Today, continued periodic follow-up of patients treated for colorectal cancer (CRC) seems often to be routine because of tradition, rather than its demonstrated value. Recently, the Norwegian Gastrointestinal Cancer Group (NGICG) has recommended a standard surveillance programme in this malignancy. In this protocol patients are suggested followed for four years with CEA monitoring, ultrasound of the liver, chest radiograph and colonoscopy at regular intervals. MATERIALS AND METHODS: In this study, the cost-effectiveness of this programme was addressed employing Norwegian cost data and data from the Cancer Registry of Norway. Clinical data from the existing English language literature was used in the analysis. RESULTS: The basic cost of the NGICG recommended programme was 1,232 Pounds per patient. Including extended investigation due to suspected relapse in 45% of cases, the figure raised to 1,943 Pounds per patient. The cost per life year saved was indicated to 9,525 Pounds-16,192 Pounds. The corresponding cost per quality adjusted life year (QALY) was indicated to 11,476 Pounds-19,508 Pounds. CONCLUSION: We conclude the NGICG recommended follow-up programme in CRC cost-effective. Excluding CEA monitoring may improve the cost-effectiveness.

Tumor markers and lung cancer: guidelines in a cost-limited medical organization.

The aim of our study was to evaluate the cost of the tumor marker assays most widely used in pneumological practice and the effectiveness of the percentage of DRG-based reimbursements absorbed by these assays. For this purpose we assessed the cost of lung tumor marker assays in Emilia Romagna compared to the DRG-based reimbursement of inpatients affected by lung diseases in whom the use of tumor markers is indicated. As an example, we evaluated the cost/effectiveness of the CEA assay in the differential diagnosis of 68 pleural effusions from 46 patients (20 benign diseases, 26 malignant). Because the CEA assay was not a substitute for cytology when this was not diagnostic, 41.3% of the resources were not efficiently spent. If the marker assay had been performed only in cases with negative cytology, we could have spared 14 of 46 tests. Moreover, since the expense lies predominantly in the cost of reagents (81.23%), we suggest as a routine procedure to collect and store samples for tumor marker assay in all cases; the test should be performed in a selected population of patients with negative cytology and "suspect" clinical outcome.

Diagnostic value of the tumor markers in breast cancer.

The use of the most common tumor markers in breast cancer was reassessed in terms of cost effectiveness and the validity of their predictive information during the evaluation of the patients. Sera from 159 patients were studied. Acceptable diagnostic specificity was found only for CA 15-3. In predicting the presence of metastases the combination of CA 15-3 and CEA was observed to correlate with lymph node metastases. Introduction of MCA did not result in diagnostic improvement. Our results suggest that in practice a diagnostic panel for breast cancer can be confined to CA 15-3 and CEA.

An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer.

OBJECTIVE: To determine the effectiveness of carcinoembryonic antigen (CEA) monitoring in detecting surgically curable recurrence of colon cancer. DESIGN: Clinical data were collected from a national surgical adjuvant trial in which CEA monitoring was elective. SETTING: Cancer centers, universities, and community clinics. PATIENTS: A total of 1216 patients with resected colon cancer, 1017 (84%) of whom had CEA monitoring. MAIN OUTCOME MEASURES: Sensitivity and specificity of CEA testing for cancer recurrence and CEA-motivated diagnostic and surgical interventions and their end results. RESULTS: Among 417 monitored patients with recurrence, 59% had a preceding elevation of CEA concentration. Sixteen percent of 600 patients without recurrence showed a false-positive test result. Carcinoembryonic antigen testing was most sensitive for hepatic or retroperitoneal metastasis and relatively insensitive for local, pulmonary, or peritoneal involvement. Surgical explorations were performed in 115 patients with CEA elevations, and 47 recurrences, usually hepatic, were resected with curative intent. On the other hand, 38 patients with normal CEA concentrations and 23 patients not monitored also underwent such resections--usually for pulmonary or local recurrence. Of all CEA-monitored patients, 2.3% are alive and disease free more than 1 year after salvage surgery (2.9% of those with CEA elevations and 1.9% of those with no elevations). Of patients with no CEA monitoring, 2.0% are also alive and disease free more than 1 year after salvage surgery. CONCLUSIONS: Cancer cures attributable to CEA monitoring are, at best, infrequent. It is questionable whether this small gain justifies the substantial cost in dollars and physical and emotional stress that this intervention may cause for patients.

Cost/effectiveness ratio of carcinoembryonic antigen--importance of adequacy of routine requests of tumor markers.

Since 1987 we have been evaluating the cost/effectiveness ratio of tumor markers using carcinoembryonic antigen (CEA) as a leading indicator. Preliminary to the evaluation of cost/effectiveness ratio we verified the fitness of CEA requests to the proper clinical problems in order to identify any bias of cost due to inadequate CEA use. 2677 CEA orders were evaluated in 1987. The percentage of inadequate requests was very high (43%). Therefore, it seemed not advisable to carry out the evaluation of cost/effectiveness ratio, while educational actions (divulgation of informative material, service of telephone consultation) were addressed to the physicians of the geographic area of laboratory users. In 1991 the adequacy of CEA requests was reevaluated. The percentage of inadequate requests on 2647 orders was 29.4%. This result, although not yet satisfactory, suggests that proper educational programs may probably improve the fitness of tumor marker requests to correct clinical problems. Additional educational actions are mandatory to further reduce the rate of inadequate tumor marker orders.