Brigitte A.B. Essers

Surgical excision versus Mohs' micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years' follow-up

BACKGROUNDnBasal-cell carcinoma (BCC) is the most common form of skin cancer and its incidence is still rising worldwide. Surgery is the most frequently used treatment for BCC, but large randomised controlled trials with 5-year follow-up to compare treatment modalities are rare. We did a prospective randomised controlled trial to compare the effectiveness of surgical excision with Mohs micrographic surgery (MMS) for the treatment of primary and recurrent facial BCC.nnnMETHODSnBetween Oct 5, 1999, and Feb 27, 2002, 408 primary BCCs (pBCCs) and 204 recurrent BCCs (rBCCs) in patients from seven hospitals in the Netherlands were randomly assigned to surgical excision or MMS. Randomisation and allocation was done separately for both groups by a computer-generated allocation scheme. Tumours had a follow-up of 5 years. Analyses were done on an intention-to-treat basis. The primary outcome was recurrence of carcinoma, diagnosed clinically by visual inspection with histological confirmation. Secondary outcomes were determinants of failure and cost-effectiveness. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN65009900.nnnFINDINGSnOf the 397 pBCCs that were treated, 127 pBCCs in 113 patients were lost to follow-up. Of the 11 recurrences that occurred in patients with pBCC, seven (4.1%) occurred in patients treated with surgical excision and four (2.5%) occurred in patients treated with MMS (log-rank test chi(2) 0.718, p=0.397). Of the 202 rBCCs that were treated, 56 BCCs in 52 patients were lost to follow-up. Two BCCs (2.4%) in two patients treated with MMS recurred, versus ten BCCs (12.1%) in ten patients treated with surgical excision (log-rank test chi(2) 5.958, p=0.015). The difference in the number of recurrences between treatments was not significant for pBCC, but significantly favoured MMS in rBCC. In pBCC, Cox-regression analysis showed no significant effects from risk factors measured in the study. In rBCC, aggressive histological subtype was a significant risk factor for recurrence in the Cox-regression analysis. For pBCC, total treatment costs were euro1248 for MMS and euro990 for surgical excision, whereas for rBCC, treatment costs were euro1284 and euro1043, respectively. Dividing the difference in costs between MMS and surgical excision by their difference in effectiveness leads to an incremental cost-effectiveness ratio of euro23 454 for pBCC and euro3171 for rBCC.nnnINTERPRETATIONnMMS is preferred over surgical excision for the treatment of facial rBCC, on the basis of significantly fewer recurrences after MMS than after surgical excision. However, because there was no significant difference in recurrence of pBCC between treatment groups, treatment with surgical excision is probably sufficient in most cases of pBCC.

Surgical excision vs Mohs' micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial

BACKGROUNDnRates of recurrence of facial basal-cell carcinoma are consistently lower after Mohs micrographic surgery (MMS) than after other treatments, such as surgical excision (SE). However, MMS is more time-consuming and therefore more expensive than SE. We investigated the types of facial basal-cell carcinomas in which MMS was more effective than SE.nnnMETHODSn408 primary and 204 recurrent facial carcinomas (374 and 191 patients, respectively) were analysed separately in this prospective randomised study. Patients were assigned SE or MMS (each 204 primary, 102 recurrent), and received treatment at two hospitals in the Netherlands. The primary outcome was recurrence of carcinoma. Analysis was by intention to treat.nnnFINDINGSnOf the basal-cell carcinomas included in the trial, 397 primary (198 MMS, 199 SE) and 201 recurrent (99, 102) tumours were actually treated. Of patients with primary carcinomas, 21 had both MMS and SE on different tumours. Nine with recurrent carcinomas had both treatments on different skin tumours. 66 primary and 13 recurrent carcinomas were lost to follow-up. Of the primary carcinomas, five (3%) recurred after SE compared with three (2%) after MMS during 30 months of follow-up. Of the recurrent carcinomas, three (3%) recurred after SE and none after MMS during 18 months of follow-up. Four recurrent carcinomas randomly assigned to the SE group were treated with MMS. Although both differences favoured MMS, they were not significant (primary, difference 1% [95% CI -2.5% to 3.7%], p=0.724; recurrent, 3.2% [-2.0% to 5.0%], p=0.119). Total operative costs of MMS were higher than those of SE (primary 405.79 Euros vs 216.86 Euros, recurrent 489.06 Euros vs 323.49 Euros; both p<0.001).nnnINTERPRETATIONnNo definitive conclusion on recurrence rates of primary or recurrent basal-cell carcinomas is yet possible. Although recurrence rates were lower after MMS than after SE, the differences were not significant.

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial

BACKGROUNDnSuperficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma.nnnMETHODSnIn this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845).nnnFINDINGSn601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting.nnnINTERPRETATIONnTopical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients.nnnFUNDINGnGrant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial

BACKGROUNDnIntravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of the AMACING trial.nnnMETHODSnAMACING is a prospective, randomised, phase 3, parallel-group, open-label, non-inferiority trial of patients at risk of contrast-induced nephropathy according to current guidelines. High-risk patients (with an estimated glomerular filtration rate [eGFR] of 30-59 mL per min/1·73 m2) aged 18 years and older, undergoing an elective procedure requiring iodinated contrast material administration at Maastricht University Medical Centre, the Netherlands, were randomly assigned (1:1) to receive intravenous 0·9% NaCl or no prophylaxis. We excluded patients with eGFR lower than 30 mL per min/1·73 m2, previous dialysis, or no referral for intravenous hydration. Randomisation was stratified by predefined risk factors. The primary outcome was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine from baseline of more than 25% or 44 μmol/L within 2-6 days of contrast exposure, and cost-effectiveness of no prophylaxis compared with intravenous hydration in the prevention of contrast-induced nephropathy. We measured serum creatinine immediately before, 2-6 days, and 26-35 days after contrast-material exposure. Laboratory personnel were masked to treatment allocation. Adverse events and use of resources were systematically recorded. The non-inferiority margin was set at 2·1%. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT02106234.nnnFINDINGSnBetween June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n=332) or intravenous hydration (n=328). 2-6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2·6%) of 307 non-hydrated patients and in eight (2·7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was -0·10% (one-sided 95% CI -2·25 to 2·06; one-tailed p=0·4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5·5%) of 328 patients had complications associated with intravenous hydration.nnnINTERPRETATIONnWe found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration according to current clinical practice guidelines.nnnFUNDINGnStichting de Weijerhorst.

Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial

BACKGROUND: Standard treatment of newly diagnosed HFE hemochromatosis patients is phlebotomy. Erythrocytapheresis provides a new therapeutic modality that can remove up to three times more red blood cells per single procedure and could thus have a clinical and economic benefit.

Transferability of model-based economic evaluations: the case of trastuzumab for the adjuvant treatment of HER2-positive early breast cancer in the Netherlands.

INTRODUCTIONnGeographic transferability of model-based cost-effectiveness results may facilitate and shorten the reimbursement process of new pharmaceuticals. This study provides a real world example of transferring a cost-effectiveness study of trastuzumab for the adjuvant treatment of HER2-positive early breast cancer from the United Kingdom to The Netherlands.nnnMETHODSnThree successive steps were taken. Step 1: Collect available information with regard to the original model, and assess transferability using existing checklists. Step 2: Adapt transferability-limiting factors. Step 3: Obtain a country-specific estimate of cost-effectiveness.nnnRESULTSnThe structure of the UK model was transferable, although some of the model inputs needed adaptation. From a health-care perspective, the Dutch estimate amounted to euro5828/quality-adjusted life-year gained. From a societal perspective, the incremental cost-effectiveness ratio was dominant.nnnCONCLUSIONnTransferability of a model-based UK-study in three steps proved to be an efficient method to provide an early indication of the cost-effectiveness of trastuzumab and has led to the provisional reimbursement of the treatment.

Mandatory imaging cuts costs and reduces the rate of unnecessary surgeries in the diagnostic work-up of patients suspected of having appendicitis

AbstractObjectiveTo evaluate whether mandatory imaging is an effective strategy in suspected appendicitis for reducing unnecessary surgery and costs.MethodsIn 2010, guidelines were implemented in The Netherlands recommending the mandatory use of preoperative imaging to confirm/refute clinically suspected appendicitis. This retrospective study included 1,556 consecutive patients with clinically suspected appendicitis in 2008–2009 (756 patients/group I) and 2011–2012 (800 patients/group II). Imaging use (none/US/CT and/or MRI) was recorded. Additional parameters were: complications, medical costs, surgical and histopathological findings. The primary study endpoint was the number of unnecessary surgeries before and after guideline implementation.ResultsAfter clinical examination by a surgeon, 509/756 patients in group I and 540/800 patients in group II were still suspected of having appendicitis. In group I, 58.5% received preoperative imaging (42% US/12.8% CT/3.7% both), compared with 98.7% after the guidelines (61.6% US/4.4% CT/ 32.6% both). The percentage of unnecessary surgeries before the guidelines was 22.9%. After implementation, it dropped significantly to 6.2% (p<0.001). The surgical complication rate dropped from 19.9% to 14.2%. The average cost-per-patient decreased by 594 € from 2,482 to 1,888 € (CL:−1081; −143).ConclusionIncreased use of imaging in the diagnostic work-up of patients with clinically suspected appendicitis reduced the rate of negative appendectomies, surgical complications and costs.Key Points• The 2010 Dutch guidelines recommend mandatory imaging in the work-up of appendicitis.n • This led to a considerable increase in the use of preoperative imaging.n • Mandatory imaging led to reduction in unnecessary surgeries and surgical complications.n • Use of mandatory imaging seems to reduce health care costs.

Three-Year Follow-Up Results of Photodynamic Therapy vs. Imiquimod vs. Fluorouracil for Treatment of Superficial Basal Cell Carcinoma: A Single-Blind, Noninferiority, Randomized Controlled Trial

A randomized controlled trial including 601 patients previously showed that the effectiveness of imiquimod and fluorouracil cream were not inferior to methyl aminolevulinate photodynamic therapy (MAL-PDT) in patients with superficial basal cell carcinoma after 1 year of follow-up. We now present the 3-year follow-up results. The probability of tumor-free survival at 3 years post-treatment was 58.0% for MAL-PDT (95% confidence interval [CI]xa0= 47.8-66.9), 79.7% for imiquimod (95% CIxa0= 71.6-85.7), and 68.2% for fluorouracil (95% CIxa0= 58.1-76.3). The hazard ratio for treatment failure comparing imiquimod with MAL-PDT was 0.50 (95% CIxa0= 0.33-0.76, Pxa0= 0.001). Comparison of fluorouracil with MAL-PDT and fluorouracil with imiquimod showed hazard ratios of 0.73 (95% CIxa0= 0.51-1.05, Pxa0= 0.092) and 0.68 (95% CIxa0= 0.44-1.06, Pxa0= 0.091), respectively. Subgroup analysis showed a higher probability of treatment success for imiquimod versus MAL-PDT in all subgroups with the exception of elderly patients with superficial basal cell carcinoma on the lower extremities. In this subgroup, the risk difference in tumor-free survival was 57.6% in favor of MAL-PDT. In conclusion, according to results at 3 years post-treatment, imiquimod is superior and fluorouracil not inferior to MAL-PDT in treatment of superficial basal cell carcinoma.

Does the Inclusion of a Cost Attribute Result in Different Preferences for the Surgical Treatment of Primary Basal Cell Carcinoma?: A Comparison of Two Discrete-Choice Experiments

Background: Nowadays, an increasing number of discrete-choice experiments (DCEs) incorporate cost as an attribute. However, the inclusion of a cost attribute, particularly within collectively funded healthcare systems, can be challenging because health services or goods are generally not traded in a market situation and individuals are not used to paying for a service or a good at the point of consumption.Objective: To examine whether the inclusion of a cost attribute in a DCE results in different preferences regarding a surgical treatment for primary basal cell carcinoma (BCC) compared with a DCE without a cost attribute.Methods: A randomized study was performed in which the impact of a cost attribute on the general public’s preferences for a surgical treatment (Mohs micrographic surgery [MMS] or standard excision [SE]) to remove BCC was examined. This was done by comparing the outcomes of two DCEs, one with a cost attribute (DCE_cost) and one without (DCE_nocost). Six attributes (recurrence, re-excision, travel time, surgical time, waiting time for surgical results, costs) and their levels were selected, based on results of a clinical trial, a cost-effectiveness study, a review and a focus group of patients who had recently received treatment for BCC. Outcomes of both DCEs were compared in terms of theoretical validity, relative importance of the attributes and the rank order of preferences.Results: A total of 615 respondents (n = 303 for DCE_nocost; n = 312 for DCE_cost) were interviewed by telephone. This gave an overall response rate of 38%.Respondents in DCE_nocost preferred a surgical treatment with a lower probability of recurrence, lower surgery time, lower waiting time and no risk for a re-excision. Respondents in DCE_cost showed the same preferences, but also preferred a treatment with less travel time and lower costs. Overall, respondents in both DCEs showed the same preference for a surgical treatment: MMS was preferred over SE.Conclusion: Results suggest that, in this population, the inclusion of a cost attribute in a DCE leads to the same preference regarding a surgical treatment to remove BCC as a DCE without a cost attribute. However, further research in different settings is needed to confirm these findings.

Assessing the public's preference for surgical treatment of primary basal cell carcinoma: a discrete-choice experiment in the south of the Netherlands.

BACKGROUND Basal cell carcinoma (BCC) is a slowly growing nonmelanoma type of skin cancer that often is located on the face. Different therapies are available to treat BCC, of which surgical excision (SE) and Mohs micrographic surgery (MMS) are the most frequently used surgical procedures. OBJECTIVES To examine which attributes of a surgical treatment the general public values as important and to determine the incremental willingness to pay for MMS versus SE. METHODS A discrete‐choice experiment (DCE) was conducted among members of the general public to examine which attributes of a surgical treatment for primary BCC are valued as important. In addition, based on the attributes included in the experiment, the willingness to pay for MMS versus SE was determined. RESULTS Respondents (N=312) preferred a treatment with a lower recurrence rate, shorter surgery time, shorter travelling time, shorter waiting time, no risk for re‐excision, and lower cost. The incremental willingness to pay for MMS was 847 euro (