Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial.

PURPOSE: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported. METHODS: In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial. RESULTS: Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer. CONCLUSION: Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.

Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial.

PURPOSE: Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven. PATIENTS AND METHODS: In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat. RESULTS: Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% (P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% (P = .096). CONCLUSION: Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.

Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial.

BACKGROUND: Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2-7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy. METHODS/DESIGN: The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m(2)/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response. DISCUSSION: The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer. TRIAL REGISTRATION: Trial open for accrual: 3 April 2013 The Netherlands National Trial Register - NTR3709 (8 November 2012) EU Clinical Trials Register - 2012-003181-40 (11 December 2012).

The use of multi-criteria decision analysis weight elicitation techniques in patients with mild cognitive impairment: a pilot study.

OBJECTIVE: To test the applicability of multi-criteria decision analysis preference elicitation techniques in cognitively impaired individuals. METHOD: A convenience sample of 16 cognitively impaired subjects and 12 healthy controls was asked to participate in a small pilot study. The subjects determined the relative importance of four decision criteria using five different weight elicitation techniques, namely simple multi-attribute rating technique, simple multi-attribute rating technique using swing weights, Kepner-Tregoe weighting, the analytical hierarchical process, and conjoint analysis. RESULTS: Conjoint analysis was judged to be the easiest method for weight elicitation in the control group (Z = 10.00; p = 0.04), while no significant differences in difficulty rating between methods was found in cognitively impaired subjects. Conjoint analysis elicitates weights and rankings significantly different from other methods. Subjectively, cognitively impaired subjects were positive about the use of the weight elicitation techniques. However, it seems the use of swing weights can result in the employment of shortcut strategies. CONCLUSION: The results of this pilot study suggest that individuals with mild cognitive impairment are willing and able to use multi-criteria elicitation methods to determine criteria weights in a decision context, although no preference for a method was found. The same methodologic and practical issues can be identified in cognitively impaired individuals as in healthy controls and the choice of method is mostly determined by the decision context.

The effect of fear of movement on muscle activation in posttraumatic neck pain disability.

Studies using surface electromyography have demonstrated a reorganization of muscle activation patterns of the neck and shoulder muscles in patients with posttraumatic neck pain disability. The neurophysiologically oriented "pain adaptation" model explains this reorganization as a useful adaptation to prevent further pain and injury. The cognitive-behavioral-oriented "fear avoidance" model suggests that fear of movement, in addition to the effects of pain, modulates the muscle activation level. We analyzed the extent to which pain and fear of movement influenced the activation patterns of the upper trapezius muscle during the transition from acute to chronic posttraumatic neck pain. Ninety-two people with an acute traumatic neck injury after a motor vehicle accident were followed up for 24 weeks. Visual analog scale ratings of pain intensity, response on the Tampa Scale of Kinesophobia--fear of movement, and surface electromyography of the upper trapezius muscles during a submaximal isometric physical task were obtained at 1, 4, 8, 12, and 24 weeks after the motor vehicle accident. Multilevel analysis revealed that an increased level of both fear of movement (t value=-2.19, P=0.030) and pain intensity (t value=-2.94, P=0.004) were independently associated with a decreased level of muscle activation. Moreover, the results suggest that the association between fear of movement and lower muscle activity level is stronger in patients reporting high pain intensity (t value=2.15, P=0.033). The contribution of pain intensity to the muscle activation level appeared to decrease over time after the trauma (t value=2.58, P=0.011). The results support both the "pain adaptation" and the "fear avoidance" models. It is likely that the decrease in muscle activation level is aimed at "avoiding" the use of painful muscles.

A preliminary economic evaluation of percutaneous neuromuscular electrical stimulation in the treatment of hemiplegic shoulder pain.

OBJECTIVE: The objective of this study was to compare the cost-effectiveness of various treatment modalities for hemiplegic shoulder pain. DESIGN: A stage II economic evaluation. MAIN OUTCOME MEASURES: Incremental cost effectiveness ratio of P-NMES, compared to slings and anti-inflammatory injections. RESULTS: The incremental cost effectiveness ratio (ICER) of p-NMES, compared to anti-inflammatory injections is 6,061 euro(+/-3,285). The incremental cost of the first quality-adjusted life year after implantation of the P-NMES device compared to anti-inflammatory injections is 33,007 euro (+/-5,434). This decreases to approximately 7,000 euro after 5 years, and to approximately 5,000 euro after 10 survival years. CONCLUSION: In this early evaluation, P-NMES seems to be cost-effective according to known guidelines. Treatment with P-NMES is recommended for patients with chronic HSP.