Patty J. Nelemans

Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data

BACKGROUND Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15-27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR. METHODS In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test. FINDINGS 484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0-277). 5-year crude disease-free survival was 83.3% (95% CI 78.8-87.0) for patients with pCR (61/419 patients had disease recurrence) and 65.6% (63.6-68.0) for those without pCR (747/2263; HR 0.44, 95% CI 0.34-0.57; p<0.0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0.54 (95% CI 0.40-0.73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0.91 (95% CI 0.73-1.12). The effect of pCR on disease-free survival was not modified by other prognostic factors. INTERPRETATION Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival. FUNDING None.

Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer

PURPOSE Neoadjuvant chemoradiotherapy for rectal cancer can result in complete disappearance of tumor and involved nodes. In patients without residual tumor on imaging and endoscopy (clinical complete response [cCR]) a wait-and-see-policy (omission of surgery with follow-up) might be considered instead of surgery. The purpose of this prospective cohort study was to evaluate feasibility and safety of a wait-and-see policy with strict selection criteria and follow-up. PATIENTS AND METHODS Patients with a cCR after chemoradiotherapy were prospectively selected for the wait-and-see policy with magnetic resonance imaging (MRI) and endoscopy plus biopsies. Follow-up was performed 3 to 6 monthly and consisted of MRI, endoscopy, and computed tomography scans. A control group of patients with a pathologic complete response (pCR) after surgery was identified from a prospective cohort study. Functional outcome was measured with the Memorial Sloan-Kettering Cancer Center (MSKCC) bowel function questionnaire and Wexner incontinence score. Long-term outcome was estimated by using Kaplan-Meier curves. RESULTS Twenty-one patients with cCR were included in the wait-and-see policy group. Mean follow-up was 25 ± 19 months. One patient developed a local recurrence and had surgery as salvage treatment. The other 20 patients are alive without disease. The control group consisted of 20 patients with a pCR after surgery who had a mean follow-up of 35 ± 23 months. For these patients with a pCR, cumulative probabilities of 2-year disease-free survival and overall survival were 93% and 91%, respectively. CONCLUSION A wait-and-see policy with strict selection criteria, up-to-date imaging techniques, and follow-up is feasible and results in promising outcome at least as good as that of patients with a pCR after surgery. The proposed selection criteria and follow-up could form the basis for future randomized studies.

Injection Therapy for Subacute and Chronic Low Back Pain : An Updated Cochrane Review

Study Design. A systematic review of randomized controlled trials (RCTs). Objective. To determine if injection therapy is more effective than placebo or other treatments for patients with subacute or chronic low back pain. Summary of Background Data. The effectiveness of injection therapy for low back pain is still debatable. Heterogeneity of target tissue, pharmacological agent, and dosage, generally found in RCTs, point to the need for clinically valid comparisons in a literature synthesis. Methods. We updated the search of the earlier systematic review and searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases up to March 2007 for relevant trials reported in English, French, German, Dutch, and Nordic languages. We also screened references from trials identified. RCTs on the effects of injection therapy involving epidural, facet, or local sites for subacute or chronic low back pain were included. Studies that compared the effects of intradiscal injections, prolotherapy, or ozone therapy with other treatments were excluded unless injection therapy with another pharmaceutical agent (no placebo treatment) was part of one of the treatment arms. Studies about injections in sacroiliac joints and studies evaluating the effects of epidural steroids for radicular pain were also excluded. Results. Eighteen trials (1179 participants) were included in this review. The injection sites varied from epidural sites and facet joints (i.e. intra-articular injections, peri-articular injections and nerve blocks) to local sites (i.e. tender-and trigger points). The drugs that were studied consisted of corticosteroids, local anesthetics, and a variety of other drugs. The methodologic quality of the trials was limited with 10 of 18 trials rated as having a high methodologic quality. Statistical pooling was not possible because of clinical heterogeneity in the trials. Overall, the results indicated that there is no strong evidence for or against the use of any type of injection therapy. Conclusion. There is insufficient evidence to support the use of injection therapy in subacute and chronic lowback pain. However, it cannot be ruled out that specific subgroups of patients may respond to a specific type of injection therapy.

Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review.

Large differences in clinical response to selective serotonin reuptake inhibitors (SSRIs) are observed in depressive patients with different genotypes. Quantification of these differences is needed to decide if genetic testing prior to antidepressant treatment is useful. We conducted a systematic review of the literature on the influence of polymorphisms in the serotonin transporter gene (SERTPR (or 5-HTTLPR) and STin2) on SSRI response. Studies were identified by the use of MEDLINE, EmBase and PsycINFO, references of articles, reviews and information from pharmaceutical companies. Nine studies assessing the influence of SERTPR or STin2 on treatment response were included. Outcome was expressed as the percentage of decrease in depression score (HAM-D or MADRS) or as the percentage of responders (≥50% reduction on the depression scale). Both study methodologies and study outcomes showed large heterogeneity. Weighted mean decreases in depression score for patients with the s/s, s/l and l/l genotypes were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6 and 48.3% at week 6. Among Caucasian patients, both mean decrease in depression score and response rate were lowest in the s/s group, while among Asian patients, results were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype of the STin2 polymorphism and 80.7% for the 12/12 genotype (χ2=27.8, P<0.001) (only Asians). The available evidence points to a less favourable response to SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among (Asian) patients with the STin2 10/12 genotype. In view of the scarcity and heterogeneity of the studies, however, current information is insufficiently reliable as a basis for implementing genetic testing in the diagnostic work-up of the depressive patient.

Facts and fiction of poor compliance as a cause of inadequate blood pressure control: a systematic review.

Objective(i) To obtain an overview of measured compliance with antihypertensive medication; (ii) to explore sources of variation in measured compliance percentages between studies; and (iii) to investigate whether studies can establish a relationship between compliance and achieved blood pressure.St

Influence of Infrarenal Neck Length on Outcome of Endovascular Abdominal Aortic Aneurysm Repair

Purpose: To evaluate the influence of the infrarenal neck length on clinical outcome after endovascular abdominal aortic aneurysm repair (EVAR). Methods: Data were analyzed from 3499 patients enrolled in the EUROSTAR registry between January 1999 and April 2005 who underwent EVAR with a Talent or Zenith endograft and had detailed morphological data recorded. The study cohort was divided into 3 groups according to infrarenal neck length: >15 mm (reference group A, n=2822), 11 to 15 mm (group B, n=485), and ≤10 mm (group C, n=192). Uni- and multivariate analyses were performed to evaluate differences in clinical outcomes among the study groups. Results: After correction for confounders, proximal type I endoleak within 30 days occurred in 10.9% of group C compared to 2.6% of group A (OR 4.46, 95% CI 2.61 to 7.61). Within 48 months of follow-up (median 12 months), the incidence of proximal endoleaks was higher in groups B (9.6%; HR 1.98, 95% CI 1.16 to 3.38) and C (11.3%; HR 2.132, 95% CI 1.17 to 4.60) compared to group A (3.4%). Conclusion: Our study indicates that endovascular treatment of abdominal aortic aneurysms with infrarenal neck length <15 mm is associated with significantly increased risk of short- and midterm proximal endoleaks after EVAR. The greater risk of proximal endoleaks should be weighed against the risks of alternative treatment modalities.

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

BACKGROUND Superficial 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. METHODS In 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). FINDINGS 601 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. INTERPRETATION Topical 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. FUNDING Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials

Background  Several noninvasive treatment modalities are available for superficial basal cell carcinoma (sBCC).

Everyday Cognitive Failure in Sarcoidosis: The Prevalence and the Effect of Anti-TNF-α Treatment

Background: Cognitive symptoms, such as concentration problems, are frequently recorded by sarcoidosis patients. Objectives: The aim of this study was to assess the prevalence of perceived everyday cognitive failure in sarcoidosis patients and healthy controls. Furthermore, the effect of treatment on cognitive functioning was examined. Methods: The study included 343 sarcoidosis patients (44.6% females; age 49.3 ± 11.0 years). They completed the Cognitive Failure Questionnaire (CFQ) and Fatigue Assessment Scale (FAS) at baseline and the 6-month follow-up to evaluate the effect of treatment on cognitive functioning. The control group consisted of 343 age- and sex-matched healthy controls. Results: The mean CFQ score was significantly higher in sarcoidosis patients (37.3 ± 16.1) compared with the controls (31.3 ± 10.1; p < 0.0001).A high CFQ sore (≧43) was found in 35.0% of the patients and only 14.3% of the controls. No relation with disease severity and duration, or disease location was found. The proportion of patients receiving treatment did not differ among the groups with high and normal CFQ score. At the 6-month follow-up, only patients recently treated with anti-TNF-α therapy (n = 42) demonstrated a significant improvement in the CFQ score (Δ –7.07 ± 7.23) compared with the untreated patients (Δ –0.08 ± 9.35) and patients treated with prednisone with or without methotrexate (Δ 1.67 ± 9.22; p < 0.0001). After adjustment for the concomitant decrease in fatigue, the effect of anti-TNF-α therapy remained high and significant. Conclusions: Subjective cognitive failure is a substantial problem in sarcoidosis patients regardless of disease severity. Anti-TNF-α therapy had a positive effect on cognition, fatigue and other symptoms of sarcoidosis.

The effect of medical elastic compression stockings with different slope values on edema. Measurements underneath three different types of stockings.

Background. Medical elastic compression stockings are widely used in venous diseases. Their effects on the venous system have been shown in the past. Up to now, little is known about the slope or stiffness factor of stockings. Objective. To evaluate the effect of different slope and stiffness factors of medical elastic compression stockings on the venous system. Methods. Examinations were carried out in 29 legs of 25 different patients (12 men, 13 women) with a mean age of 66.0 years. All patients were known with chronic venous insufficiency. On all these patients three different elastic medical compression stockings were tested; one with a low slope, one with a high slope, and one with a low slope but a higher pressure at the ankle. The tests were carried out by determining capillary filtration rate (CFR) with air‐plethysmography (APG) while wearing the stockings. Results. The mean value of the CFR without wearing a stocking was 4.65 ml/min ( SD= 1.68), with Compriform (low slope, 30 mmHg) the mean CFR was 3.54 ml/min ( SD= 1.22), with Bellavar (high slope, 30 mmHg) a mean CFR of 3.15 ml/min (SD = 1.17) was found, and the mean CFR related to Fast‐fit (low slope, 34.5 mmHg) was 3.02 ml/min ( SD= 1.12). There is a highly statistically significant difference in CFR between no stockings and wearing a stocking (paired Students t‐test; P < 0.01). Regarding the individual stocking, there is a highly statistically significant difference in CFR between the Compriform and the other two stockings (paired Students t‐test; P < 0.01). Between Bellavar and the Fast‐fit the difference was not statistically significant. Conclusions. There is a statistically significant difference in CFR, and consequently in the development of edema, between not wearing an elastic compression stocking and wearing an elastic compression stocking. There is also a statistically significant difference in CFR between elastic compression stockings with the same compression, but a low slope profile and a high slope profile. Stockings with a low slope, but a higher compression may perform as well as stockings with a higher slope but a lower compression in reducing the CFR. In patients with a strong tendency to develop edema it may be advisable to prescribe stockings with a high slope profile.