Combination Drug Therapy for the Management of Chronic Neuropathic Pain.

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.

Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study.

INTRODUCTION: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. METHODS: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. RESULTS: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. CONCLUSIONS: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51.

Effect of Multimodal Prehabilitation on Reducing Postoperative Complications and Enhancing Functional Capacity Following Colorectal Cancer Surgery: The PREHAB Randomized Clinical Trial.

Importance: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient's condition in the weeks prior to surgery may attenuate these unfavorable sequelae. Objective: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery. Design, Setting, and Participants: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic. Interventions: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed. Main Outcomes and Measures: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively. Results: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, -1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care. Conclusions and Relevance: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care. Trial Registration: trialregister.nl Identifier: NTR5947.

Neoadjuvant Prehabilitation Therapy for Locally Advanced Non-Small-Cell Lung Cancer: Optimizing Outcomes Throughout the Trajectory of Care.

BACKGROUND: Prehabilitation is well established for improving outcomes in cancer surgery. Combining prehabilitation with neoadjuvant treatments may provide an opportunity to rapidly initiate cancer-directed therapy while improving functional status in preparation for local consolidation. In this proof-of-concept study, we analyzed non-small-cell lung cancer patients who underwent simultaneous prehabilitation and neoadjuvant therapy. PATIENTS AND METHODS: We retrospectively analyzed all patients who underwent neoadjuvant treatment for non-small-cell lung cancer followed by curative intent surgery between 2015 and 2021. Patients who were screened for the prehabilitation program were identified. The screening included assessment of physical performance, nutritional status, and signs of anxiety and depression. RESULTS: We identified a total of 141 patients who underwent neoadjuvant therapy. Twenty patients were screened to undergo a prehabilitation program. Four patients did not complete the exercise program (1 surgical intervention too soon, 1 drop-out after the first session, and 2 patients were deemed fit without intervention). The postoperative median length of stay was 2 days (range 1-18). Patients improved their 6-minute-walk test despite undergoing neoadjuvant treatment by a mean of 33 meters (± 50, P = .1). Self-reported functional status (DASI) showed significant improvement by a mean of 10 points (± 11, P = .03), and HADS-anxiety-score was significantly reduced after the prehabilitation program by a mean of 1.5 points (± 1, P = .005). CONCLUSION: Neoadjuvant prehabilitation therapy is feasible and associated with encouraging results. The performance of all measures remains a logistic challenge. With multimodal strategies for lung cancer treatment becoming key to optimal outcomes, neoadjuvant prehabilitation therapy is a concept worthy of prospective multi-center evaluation.

Ketoprofen lysine salt has a better gastrointestinal and renal tolerability than ketoprofen acid: A comparative tolerability study in the Beagle dog.

Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs), the incidence of NSAID-associated adverse events has increased exponentially over the past decades. Ketoprofen (ketoprofen acid, KA) is a widely used NSAID and, like with other NSAIDs, its use can be associated with adverse effects that especially involve the gastrointestinal tract and the kidney. The salification of KA with L-lysine has led to the synthesis of ketoprofen lysine salt (KLS), which is characterized by higher solubility and a more rapid gastrointestinal absorption compared to KA. Previous studies have reported that KLS has also an increased gastric tolerance in vitro, and this is due to the inhibition of lipid peroxidation and reactive oxygen species scavenging effects of L-lysine. Here, we report in vivo tolerability/toxicity studies that were conducted prior seeking KLS marketing authorization, in which we compared KLS and KA safety profile, focusing in particular on the evaluation of the gastrointestinal and renal tolerability of the drugs administered orally to dogs. Our results demonstrate that KLS has an increased in vivo gastrointestinal tolerability compared to KA and show, for the first time, that KLS has also increased in vivo renal tolerability compared to KA, thus supporting the concept that L-lysine may counteract NSAID-induced oxidative stress-mediated gastrointestinal and renal injury.

Strategies for optimal perioperative outcomes in gastric cancer.

Cancer and surgery represent a major stress on the human body. Any condition that prevents patients from tolerating the physiological stress is a risk factor for poor outcome. There is a need to identify these impairments early in the process with a simple screening, followed by assessments that provide a holistic picture of the patient. The proposed path of multimodal prehabilitation acts synergistically with enhanced recovery after surgery care to achieve optimal patient outcomes.

Role of prehabilitation following major uro-oncologic surgery: a narrative review.

PURPOSE: Functional status and physical independence play a key role in terms of quality of life, access to treatment, and continuity of care. Surgery, a central component of cancer treatments, leads to detrimental effects on functional capacity, which can be peculiarly relevant in vulnerable patients undergoing major procedures. Prehabilitation is a multidisciplinary intervention that uses the preoperative period to prevent or attenuate treatment-related functional decline and its subsequent consequences. This paper narratively reviews the rationale and the evidence of prehabilitation for uro-oncologic surgery. METHODS: A narrative review was conducted in August 2020, aiming to: (1) identify and discuss the impact of modifiable determinants of postoperative outcomes in urology and (2) review randomized controlled trials (RCT) exploring the role of preoperative exercise, nutrition, and psychological interventions in uro-oncologic surgery. RESULTS: Eight RCTs on preoperative conditioning interventions met the inclusion criteria, focusing on radical cystectomy for bladder cancer (RC) and radical prostatectomy for prostate cancer (RP). There is strong evidence that poor physical, nutritional and psychosocial status negatively impacts on surgical outcomes. Single modality interventions, such as preoperative exercise or nutrition alone, had no effect on 'traditional' surgical outcomes as length of stay or complication. However, multimodal approaches targeting postoperative functional status have shown to be effective and safe. CONCLUSION: There is initial evidence on the effectiveness and safety of multimodal prehabilitation in preserving functional capacity following RC and RP. However, to date, outcomes such as complications and length of stay seem to be not affected by prehabilitation.

Prehabilitation Program in Elderly Patients: A Prospective Cohort Study of Patients Followed Up Postoperatively for Up to 6 Months.

The preoperative period may be an opportune period to optimize patients' physical condition with a multimodal preoperative program. The impact of a "prehabilitation" program on elderly patients is discussed. This mono-center observational cohort study included consecutively 139 patients planned for major abdominal and thoracic surgery, with 44 in the control group (age < 65) and 95 in the elderly group (age > 65). All patients followed a "prehabilitation" program including exercise training, nutritional optimization, psychological support, and behavioral change. Seventeen patients in the control group and 45 in the elderly group completed the study at six months. The 6-minute walk test (6 MWT) increased in both groups from the initial evaluation to the last (median value of 80 m (interquartile range 51) for those under 65 years; 59 m (34) for the elderly group; p = 0.114). The 6 MWT was also similar after one month of prehabilitation for both populations. The rate of postoperative complications was similar in the two groups. Prehabilitation showed equivalence in patients over 65 years of age compared to younger patients in terms of increase in functional capabilities and of postoperative evolution. This multimodal program represents a bundle of care that can benefit a frailer population.

Functional capacity of prediabetic patients: effect of multimodal prehabilitation in patients undergoing colorectal cancer resection.

BACKGROUND: Prehabilitation is the process of increasing functional capacity (FC) before surgery. Poor glycemic control is associated with worse outcomes in patients undergoing surgery. Therefore, prediabetic patients could particularly benefit from prehabilitation. METHODS: This is a pooled analysis of individual patient data from three multimodal prehabilitation trials in colorectal cancer surgery. Following a baseline assessment using the 6-minute walking test (6MWT), subjects were randomized to multimodal prehabilitation or to a control group. Participants were reassessed 24 h before surgery and 4 weeks after surgery. Prediabetes (PreDM) was defined as HbA1c 5.7%-6.4%. Multivariable logistic regression was used to adjust for potentially confounding variables. RESULTS: Participation in a prehabilitation program was the most important predictive factor of clinical improvement in FC prior to surgery (Adjusted OR 2.42, 95% CI 1.18, 4.94); prediabetes was not a statistically significant predictor of improvement in FC after adjustments for covariates. Prehabilitation attenuated the loss of FC in unadjusted analyses after surgery in prediabetic patients (PreDM Control: median change -6 m [IQR -50-20] vs PreDM Prehab: median change +25 m [IQR -20-53], p = 0.045). Adjusted analyses also suggested the protective effect against loss of FC after surgery was stronger in prediabetic patients (PreDM Prehab vs PreDM Control: OR 5.5, 95% CI: 1.2-25.8; Normo Prehab vs Normo Control: OR 1.5, 95% CI: 0.53-4.52). CONCLUSIONS: Multimodal prehabilitation favored clinical recovery of FC after surgery in CRC patients, especially prediabetic patients.

Prehabilitation in Thoracic Cancer Surgery: From Research to Standard of Care.

OBJECTIVE: To determine whether personalized, stepped prehabilitation care is a feasible, safe, and effective implementation strategy. DESIGN: Quality improvement project. Data collected prospectively from August 2018 to December 2019 were analyzed retrospectively to describe the clinical implementation of a prehabilitation care program for elective lung cancer surgery. SETTING: Single center, tertiary university hospital. PARTICIPANTS: Eighty-one consecutive adult patients living in the metropolitan area of Montreal were included if an elective resection of suspected or confirmed lung cancer was planned. INTERVENTIONS: At the earliest contemplation of surgery, the whole cohort was screened for impaired physical, nutritional, and/or psychological status. Patients screened at higher risk received dedicated assessment and personalized prehabilitation care upon specific needs. MEASUREMENTS AND MAIN RESULTS: Patients' specific needs and their access and flow through the different services were described. Prehabilitation effectiveness was evaluated using walking and exercise tests, and adverse events were monitored. Eighty-one patients were screened for functional impairments. Forty patients showed reduction of physical function, seven of them refused the specific assessment, one refused in-hospital exercise; 48 patients showed nutritional risk, eight of them refused or did not comply with nutritional therapy. Overall, 45 high-risk patients received a one-month personalized prehabilitation program: 16 partook in a trimodal program (exercise, nutrition, and psychological), and 22 received a program with both nutrition and exercise. No adverse events occurred during the study period. After prehabilitation, six-minute waking distance improved by 29.9 meters (standard deviation 47.3 m) (n = 35; p = 0.001) and the oxygen uptake at the anaerobic threshold improved by 1.6 (1.7) mL/kg/min (n = 13; p = 0.004). Length of hospital stay was two (interquartile range one-four) days in prehabilitated patients versus three (two-seven) days in the usual care group (p = 0.101). CONCLUSIONS: A personalized, stepped prehabilitation program targeting high-risk patients undergoing elective lung cancer surgery was feasible, safe, and effective.

Multimodal Prehabilitation for Lung Cancer Surgery: A Randomized Controlled Trial.

BACKGROUND: The study was conducted to determine whether a multimodal prehabilitation program enhances postoperative functional recovery compared with multimodal rehabilitation. METHODS: Patients scheduled for non-small cell lung cancer resection were randomized to 2 groups receiving home-based moderate-intensity exercise, nutritional counseling with whey protein supplementation, and anxiety-reducing strategies for 4 weeks before the operation (PREHAB, n = 52) or 8 weeks after (REHAB, n = 43). Functional capacity (FC) was measured by the 6-minute walk test (6MWT) at baseline, immediately before the operation, and 4 and 8 weeks after operation. All patients were treated according to enhanced recovery pathway guidelines. RESULTS: There was no difference in FC at any point during the perioperative period between the 2 multimodal programs. By 8 weeks after operation, both groups returned to baseline FC, and a similar proportion of patients (>75%) in both groups had recovered to their baseline. CONCLUSIONS: In patients undergoing surgical resection for lung cancer within the context of an enhanced recovery pathway, multimodal prehabilitation initiated 4 weeks before operation is as effective in recovering FC as multimodal rehabilitation.

Multimodal Prehabilitation to Enhance Functional Capacity Following Radical Cystectomy: A Randomized Controlled Trial.

BACKGROUND: In patients with bladder cancer, poor functional status has remarkable deleterious effects on postoperative outcome and prognosis. Conditioning intervention initiated before surgery has the potential to reduce functional decline attributable to surgery. Nonetheless, evidence is lacking in patients undergoing radical cystectomy. OBJECTIVE: To determine whether a preoperative multimodal intervention (prehabilitation) is feasible and effective in radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: This study, conducted at an academic tertiary health care institution, enrolled adult patients scheduled for radical cystectomy. From August 2013 to October 2017, 70 patients were randomized: 35 to multimodal prehabilitation (prehab group) and 35 to standard care (control group). INTERVENTION: Multimodal prehabilitation was a preoperative conditioning intervention including aerobic and resistance exercise, diet therapy, and relaxation techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was perioperative change in functional capacity, measured with the distance covered during a 6-min walk test (6MWD), assessed at baseline, before surgery, and at 4 and 8 wk after surgery. Data were compared using robust mixed linear models for repeated measures. RESULTS AND LIMITATIONS: Preoperative change in 6MWD compared with baseline was not significantly different between groups (prehab group 40.8 [114.0] m vs control group 9.7 (108.4) m, p=0.250). However, at 4 wk after surgery, a significant difference in functional capacity was detected (6MWD, prehab group -15.4 [142.5] m vs control group -97.9 [123.8] m, p=0.014). No intervention-related adverse effects were reported. CONCLUSIONS: Data suggested that multimodal prehabilitation resulted in faster functional recovery after radical cystectomy. PATIENT SUMMARY: After major cancer surgery, people usually feel week and tired, and have less energy to perform activities of daily living. In this study, we showed that using the time before surgery to promote exercise and good nutrition could fasten recovery after the surgical removal of the bladder.

Older frail prehabilitated patients who cannot attain a 400 m 6-min walking distance before colorectal surgery suffer more postoperative complications.

INTRODUCTION: Recent efforts to prehabilitate intermediately frail and frail (Fried frailty criteria ≥2) elective colorectal cancer patients did not influence clinical nor functional outcomes. The objective of this secondary analysis was to describe the subset of intermediately frail and frail prehabilitated patients who could not attain a minimum 400 m (a prognostic cut-point used in other patient populations) 6-min walking distance (6MWD) before elective surgery. MATERIALS AND METHODS: Secondary analysis of a randomized controlled trial. Patients participated in multimodal prehabilitation at home and in-hospital for approximately four weeks before colorectal surgery. Primary outcome was incidence of postoperative complications within 30 days of hospital discharge. RESULTS: Sixty percent of the patients who participated in prehabilitation did not reach a minimum walking distance of 400 m in 6 min before surgery. Compared to the group that attained ≥400 m 6MWD (n = 19), the <400 m group (n = 28) were older, had higher percent body fat, lower physical function, lower self-reported physical activity, higher American Society of Anesthesiologists (ASA) classification, and twice as many were in critical need of a nutrition intervention at baseline. No group differences were observed regarding frailty status (P = 0.775). Sixty-one percent of the <400 m 6MWD group experienced at least one complication within 30 days of surgery compared to 21% in the ≥400 m group (P = 0.009). CONCLUSION: Several preoperative characteristics were identified in the <400 m 6MWD group that could be useful in screening and targeting future prehabilitative treatments. Future trials should investigate use of a 400 m standard for the 6MWD as a minimal treatment target for prehabilitation.

Effect of two different pre-operative exercise training regimens before colorectal surgery on functional capacity: A randomised controlled trial.

BACKGROUND: Multimodal prehabilitation, including exercise training, nutritional therapy and anxiety reduction, has been shown to attenuate functional decline associated with surgery. Due to the growing interest in functional status as a targeted surgical outcome, a better understanding of the optimal prescription of exercise is critical. OBJECTIVE: The objective is to compare peri-operative functional trajectory in response to two different exercise training protocols within a 4-week, supervised, multimodal prehabilitation programme. DESIGN: This was a single blinded, single centre, randomised controlled study. Participants performed four assessments: at baseline, after prehabilitation (just before surgery), and at 1 and 2 months after surgery. PATIENTS: Adult patients scheduled for elective resection of nonmetastatic colorectal cancer were included provided there were no absolute contraindications to exercise nor poor language comprehension. INTERVENTION: Patients followed either high-intensity interval training (HIIT), or moderate intensity continuous training (MICT), as part of a 4-week multimodal prehabilitation programme. Both groups followed the same supervised resistance training, nutritional therapy and anxiety reduction interventions. All patients followed standardised peri-operative management. MAIN OUTCOME MEASURE: Changes in oxygen consumption at anaerobic threshold, measured with sequential cardio-pulmonary exercise testing, were assessed and compared between groups. RESULTS: Forty two patients were included in the primary analysis (HIIT n = 21 vs. MICT n = 21), with mean ±â€ŠSD age 64.5 ±â€Š11.2 years and 62% were men. At 2 months after surgery, 13/21 (62%) in HIIT and 11/21 (52%) in MICT attended the study visits. Both protocols significantly enhanced pre-operative functional capacity, with no difference between groups: mean (95% confidence interval) oxygen consumption at anaerobic threshold 1.97 (0.75 to 3.19) ml kg min in HIIT vs. 1.71 (0.56 to 2.85) in MICT, P = 0.753. At 2 months after surgery, the HIIT group showed a higher improvement in physical fitness: 2.36 (0.378 to 4.34) ml kg min, P = 0.021. No adverse events occurred during the intervention. CONCLUSION: Both MICT and HIIT enhanced pre-operative functional capacity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03361150.

Prehabilitation: the anesthesiologist's role and what is the evidence?

PURPOSE OF REVIEW: Surgery poses major threats to functional independence. Prehabilitation is a preoperative conditioning intervention that aims to prevent or attenuate surgery-related functional decline and its consequences. The present review is to summarize most recent evidence on the effectiveness of prehabilitation on key topics in cancer care, such as perioperative functional capacity, surgical and oncologic outcomes. RECENT FINDINGS: Recent studies predominantly focus on functional outcomes, demonstrating a positive effect of prehabilitation on perioperative physical fitness. SUMMARY: Prehabilitation prevents functional decline associated with major cancer surgery. Evidence is still needed to support its effectiveness in relation to postoperative complication, length of hospital stay, tumor progression, response to medical treatment, and survival. Ongoing and future research is essential to prompt the role of perioperative medicine in cancer care.

Effect of Multimodal Prehabilitation vs Postoperative Rehabilitation on 30-Day Postoperative Complications for Frail Patients Undergoing Resection of Colorectal Cancer: A Randomized Clinical Trial.

Importance: Research supports use of prehabilitation to optimize physical status before and after colorectal cancer resection, but its effect on postoperative complications remains unclear. Frail patients are a target for prehabilitation interventions owing to increased risk for poor postoperative outcomes. Objective: To assess the extent to which a prehabilitation program affects 30-day postoperative complications in frail patients undergoing colorectal cancer resection compared with postoperative rehabilitation. Design, Setting, and Participants: This single-blind, parallel-arm, superiority randomized clinical trial recruited patients undergoing colorectal cancer resection from September 7, 2015, through June 19, 2019. Patients were followed up for 4 weeks before surgery and 4 weeks after surgery at 2 university-affiliated tertiary hospitals. A total of 418 patients 65 years or older were assessed for eligibility. Of these, 298 patients were excluded (not frail [n = 290], unable to exercise [n = 3], and planned neoadjuvant treatment [n = 5]), and 120 frail patients (Fried Frailty Index,≥2) were randomized. Ten patients were excluded after randomization because they refused surgery (n = 3), died before surgery (n = 3), had no cancer (n = 1), had surgery without bowel resection (n = 1), or were switched to palliative care (n = 2). Hence, 110 patients were included in the intention-to-treat analysis (55 in the prehabilitation [Prehab] and 55 in the rehabilitation [Rehab] groups). Data were analyzed from July 25 through August 21, 2019. Interventions: Multimodal program involving exercise, nutritional, and psychological interventions initiated before (Prehab group) or after (Rehab group) surgery. All patients were treated within a standardized enhanced recovery pathway. Main Outcomes and Measures: The primary outcome included the Comprehensive Complications Index measured at 30 days after surgery. Secondary outcomes were 30-day overall and severe complications, primary and total length of hospital stay, 30-day emergency department visits and hospital readmissions, recovery of walking capacity, and patient-reported outcome measures. Results: Of 110 patients randomized, mean (SD) age was 78 (7) years; 52 (47.3%) were men and 58 (52.7%) were women; 31 (28.2%) had rectal cancer; and 87 (79.1%) underwent minimally invasive surgery. There was no between-group difference in the primary outcome measure, 30-day Comprehensive Complications Index (adjusted mean difference, -3.2; 95% CI, -11.8 to 5.3; P = .45). Secondary outcome measures were also not different between groups. Conclusions and Relevance: In frail patients undergoing colorectal cancer resection (predominantly minimally invasive) within an enhanced recovery pathway, a multimodal prehabilitation program did not affect postoperative outcomes. Alternative strategies should be considered to optimize treatment of frail patients preoperatively. Trial Registration: ClinicalTrials.gov identifier: NCT02502760.

Multiphasic Prehabilitation Across the Cancer Continuum: A Narrative Review and Conceptual Framework.

The field of cancer survivorship has significantly advanced person-centered care throughout the cancer continuum. Within cancer survivorship, the last decade has seen remarkable growth in the investigation of prehabilitation comprising pre-treatment interventions to prevent or attenuate the burden of oncologic therapies. While the majority of evidence remains in the surgical setting, prehabilitation is being adapted to target modifiable risk factors that predict poor treatment outcomes in patients receiving other systemic and localized anti-tumor treatments. Here, we propose a multiphasic approach for prehabilitation across the cancer continuum, as a conceptual framework, to encompass the variability in cancer treatment experiences while adopting the most inclusive definition of the cancer survivor.

Depression and functional status in colorectal cancer patients awaiting surgery: Impact of a multimodal prehabilitation program.

OBJECTIVE: Depression and poor functional status (FS) frequently co-occur. Though both predict adverse surgical outcomes, research examining preoperative functional performance (FP; self-reported) and functional capacity (FC; performance-based) measures in depressed cancer patients is lacking. Prehabilitation, a preoperative intervention including exercise, nutrition, and stress-reduction, may improve FC; however, whether depressed patients benefit from this intervention remains unknown. The primary objectives were to (a) assess differences in FP and FC and (b) explore the impact of prehabilitation on FC in individuals with depressive symptoms versus those without. METHOD: A secondary analysis was conducted on 172 colorectal cancer patients enrolled in three studies comparing prehabilitation with a control group (rehabilitation). Measures were collected at 4 weeks pre- and 8 weeks postoperatively. FP, FC, and psychological symptoms were assessed using the 36-Item Short Form Health Survey, Six-Minute Walk Distance (6MWD), and Hospital Anxiety and Depression Scale (HADS), respectively. Subjects were divided into three groups according to baseline psychological symptoms: no psychological-symptoms (HADS-N), anxiety-symptoms (HADS-A), or depressive-symptoms (HADS-D). Main objectives were tested using analyses of variance, chi-square tests, and multivariate logistic regression. RESULTS: At baseline, HADS-D reported lower FP, had shorter 6MWD, and a greater proportion walked ≤ 400 m. Prehabilitation was associated with significant improvements in 6MWD in HADS-D group but not in HADS-N or HADS-A groups. CONCLUSION: Poorer FS was observed in subjects with depressive symptoms, and these subjects benefited most from prehabilitation intervention. Future research could examine whether severity of depression and co-occurrence of anxiety differentially impact FS and whether prehabilitation can improve psychological symptoms and quality of life. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Improved Disease-free Survival After Prehabilitation for Colorectal Cancer Surgery.

OBJECTIVE: The objective of this study was to investigate the effect of prehabilitation on survival after colorectal cancer surgery. SUMMARY OF BACKGROUND DATA: Preoperative multimodal exercise and nutritional programs (prehabilitation) improve functional capacity and recovery following colorectal surgery. Exercise may also affect cancer outcomes by mediating the systemic inflammatory response. The effect of prehabilitation on cancer outcomes is unknown. METHODS: Pooled data from 3 prehabilitation trials (2 randomized controlled trials, 1 cohort) in patients undergoing elective, biopsy-proven, primary non-metastatic colorectal cancer surgery from 2009 to 2014 within an enhanced recovery program were analyzed. Patients were grouped into +prehab or-prehab. The primary outcomes were 5-year disease-free (DFS) and overall survival (OS). DFS and OS were analyzed using Kaplan-Meier curves and multiple Cox regression. RESULTS: A total of 202 patients were included (+prehab 104, -prehab 98). Median prehabilitation duration was 29 days (interquartile range 20-40). Patient and tumor characteristics were well-balanced (33% stage III). Postoperative complications and time to adjuvant chemotherapy were similar. Mean duration of follow-up was 60.3 months (standard deviation 26.2). DFS was similar for the combined group of stage I-III patients (P = 0.244). For stage III patients, prehabilitation was associated with improved DFS (73.4% vs 50.9%, P = 0.044). There were no differences in OS (P = 0.226). Prehabilitation independently predicted improved DFS (hazard ratio 0.45; 95% confidence interval, 0.21-0.93), adjusting for stage and other confounders. Prehabilitation did not independently predict OS. CONCLUSION: In this report, prehabilitation is associated with improved 5-year DFS in stage III colorectal cancer. This finding should be confirmed in future trials.