Effect of Multimodal Prehabilitation vs Postoperative Rehabilitation on 30-Day Postoperative Complications for Frail Patients Undergoing Resection of Colorectal Cancer

The researchers compared two groups of frail patients undergoing colorectal cancer surgery:

**Prehabilitation (Prehab) group:** A multimodal program started 4 weeks before surgery and continued for 4 weeks after surgery. The program included three components: (1) exercise (aerobic, resistance, and flexibility training), (2) nutritional counseling (protein supplementation and dietary advice), and (3) psychological support (relaxation techniques and anxiety reduction strategies).

**Rehabilitation (Rehab) group:** The exact same multimodal program, but started only after surgery (for 4 weeks postoperatively). This group received standard preoperative care without any structured intervention before surgery.

Both groups were treated within a standardized enhanced recovery pathway (ERP), which is a set of evidence-based perioperative protocols designed to speed recovery (e.g., early feeding, early mobilization, minimal opioid use).

The primary outcome was the **Comprehensive Complications Index (CCI)** at 30 days after surgery. The CCI is a single score (0–100 scale, where 0 = no complications and 100 = death) that sums all postoperative complications, weighting them by severity. This is more sensitive than simply counting whether any complication occurred.

Secondary outcomes included: overall complication rate (any complication), severe complication rate (Clavien-Dindo grade ≥ III, meaning complications requiring surgical, endoscopic, or radiological intervention), length of hospital stay (primary stay and total stay including readmissions), 30-day emergency department visits, 30-day hospital readmissions, recovery of walking capacity (measured by the 6-minute walk test), and patient-reported outcomes (quality of life, fatigue, anxiety, depression).

**Sample size:** 110 frail patients (55 per group) were included in the intention-to-treat analysis. Initially, 120 were randomized, but 10 were excluded after randomization for reasons such as refusing surgery, death before surgery, no cancer found, or switch to palliative care.

**Population:** Patients aged 65 years or older (mean age 78 years, SD 7 years) undergoing elective colorectal cancer resection (surgical removal of part of the colon or rectum). All patients were classified as frail using the Fried Frailty Index (score ≥ 2 out of 5). The Fried Frailty Index measures five components: unintentional weight loss, self-reported exhaustion, weak grip strength, slow walking speed, and low physical activity.

**Gender:** 52 men (47.3%) and 58 women (52.7%).

**Cancer type:** 31 patients (28.2%) had rectal cancer; the remainder had colon cancer.

**Surgery type:** 87 patients (79.1%) underwent minimally invasive surgery (laparoscopic or robotic), and 23 (20.9%) had open surgery.

**Setting:** Two university-affiliated tertiary hospitals in Montreal, Canada. Recruitment ran from September 7, 2015, through June 19, 2019.

**Exclusion criteria:** Patients who were not frail (Fried Frailty Index < 2), unable to exercise (e.g., severe cardiovascular or musculoskeletal limitations), or planned for neoadjuvant treatment (chemotherapy or radiation before surgery) were excluded.

**Frailty status:** Fried Frailty Index (0–5 scale, ≥2 = frail). Components measured objectively: grip strength (hand dynamometer), walking speed (timed 5-meter walk), and self-reported weight loss, exhaustion, and physical activity.

**Primary outcome – Comprehensive Complications Index (CCI):** A 0–100 scale calculated from all postoperative complications graded by the Clavien-Dindo classification (grades I–V). The CCI is computed using a formula that accounts for the number and severity of complications. A score of 0 means no complications; 100 means death. For example, a single grade II complication (requiring pharmacological treatment) gives a CCI of ~20.9; a grade IIIb complication (requiring surgical intervention under general anesthesia) gives ~33.7.

**Secondary outcomes:**

- **Overall complications:** Any Clavien-Dindo grade ≥ I complication within 30 days.

- **Severe complications:** Clavien-Dindo grade ≥ III (requiring intervention).

- **Length of hospital stay:** Days from surgery to discharge (primary stay) and total days including readmissions within 30 days.

- **Emergency department visits and readmissions:** Counts within 30 days of discharge.

- **Walking capacity:** 6-minute walk test (distance in meters walked in 6 minutes on a flat surface). Measured at baseline, preoperatively (after 4 weeks of prehab), and at 4 weeks postoperatively.

- **Patient-reported outcomes:** European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, 0–100 scale, higher = better function), Hospital Anxiety and Depression Scale (HADS, 0–21 per subscale, lower = better), and the Fatigue Severity Scale (FSS, 1–7 average, lower = less fatigue).

**Adherence monitoring:** Exercise adherence was tracked via daily logs and weekly phone calls. Nutritional adherence was assessed through protein supplement consumption logs. Psychological intervention adherence was monitored via attendance at relaxation sessions.

**Study design:** This was a single-blind, parallel-arm, superiority randomized clinical trial (RCT). Patients were randomized 1:1 to either the Prehab or Rehab group using a computer-generated random sequence with variable block sizes, stratified by hospital site and surgical approach (minimally invasive vs. open).

**Blinding:** The study was single-blind. Outcome assessors (research assistants measuring walking capacity, reviewing medical records for complications, and administering questionnaires) were blinded to group allocation. Patients and the exercise/nutrition/psychology coaches were not blinded because it was obvious whether the intervention started before or after surgery. This is a common limitation in prehabilitation trials because you cannot easily give a sham intervention.

**Duration:** The intervention lasted 4 weeks before surgery (Prehab group only) and 4 weeks after surgery (both groups). Follow-up for the primary outcome was 30 days after surgery. Total study duration per patient was approximately 8–9 weeks (4 weeks preop + surgery + 4 weeks postop).

**Statistical approach:** The primary analysis was intention-to-treat (ITT), meaning all randomized patients who underwent surgery were analyzed in their assigned group regardless of adherence. The primary outcome (CCI) was compared between groups using a linear regression model adjusted for stratification factors (hospital site and surgical approach). Secondary outcomes were analyzed using similar regression models (logistic for binary outcomes, linear for continuous). A sample size calculation determined that 55 patients per group would provide 80% power to detect a clinically meaningful difference in CCI of 15 points (SD 25) at α = 0.05.

**What this design can and cannot prove:**

**Can prove:** Because this is an RCT with random allocation, it can establish causality. If a difference were found, you could confidently say the prehabilitation program *caused* the difference in outcomes, not some confounding factor. The ITT analysis preserves randomization and gives a real-world estimate of the intervention's effect (including non-adherence). The single-blind design reduces bias in outcome measurement.

**Cannot prove:** The design cannot tell you which component of the multimodal program (exercise, nutrition, or psychology) was responsible for any effect, because they were bundled together. It also cannot tell you whether a longer prehabilitation period (e.g., 8 weeks) or a different dose of exercise would work. The lack of blinding of patients and coaches means that placebo effects or differential co-interventions (e.g., Rehab patients might have been more anxious knowing they weren't getting prehab) could theoretically influence some outcomes, especially patient-reported measures. The study was conducted at two academic hospitals in one country, so generalizability to other settings (e.g., community hospitals, different healthcare systems) is uncertain.

**Major methodological weaknesses:**

The study was underpowered for the primary outcome. The sample size calculation assumed a 15-point difference in CCI (SD 25), but the observed SD was larger (~30), and the actual difference was only 3.2 points. The study may have missed a smaller but still clinically meaningful effect.

Adherence to the prehabilitation program was not reported in detail in the abstract, but in the full text, adherence to exercise sessions was around 70–80%, meaning some patients did not fully receive the intended dose.

The Rehab group received the same program after surgery, which may have improved their recovery and reduced the apparent benefit of prehabilitation. A true control group (no intervention at all) might have shown a larger difference.

Frail patients are a heterogeneous group; the Fried Frailty Index is a simple screening tool and may not capture all dimensions of frailty relevant to surgical recovery.

**Primary outcome – Comprehensive Complications Index (CCI) at 30 days:** No significant difference between groups.

- Prehab group mean CCI: 20.9 (SD 29.7)

- Rehab group mean CCI: 24.1 (SD 30.1)

- Adjusted mean difference: -3.2 (95% CI, -11.8 to 5.3; P = .45)

- This means the Prehab group had a CCI that was, on average, 3.2 points lower (fewer complications), but the confidence interval crossed zero, and the p-value was not significant.

**Secondary outcomes – all non-significant:**

- **Overall complication rate (any complication):** Prehab 54.5% vs. Rehab 60.0% (odds ratio 0.79; 95% CI, 0.37 to 1.69; P = .55)

- **Severe complication rate (grade ≥ III):** Prehab 18.2% vs. Rehab 20.0% (odds ratio 0.89; 95% CI, 0.34 to 2.31; P = .81)

- **Primary length of hospital stay:** Prehab median 4 days (IQR 3–7) vs. Rehab median 4 days (IQR 3–7); adjusted difference not significant.

- **Total length of hospital stay (including readmissions):** Prehab median 4 days (IQR 3–7) vs. Rehab median 4 days (IQR 3–8); not significant.

- **30-day emergency department visits:** Prehab 18.2% vs. Rehab 21.8% (P = .63)

- **30-day hospital readmissions:** Prehab 9.1% vs. Rehab 12.7% (P = .54)

- **Walking capacity (6-minute walk test):** Change from baseline to 4 weeks postoperatively: Prehab improved by +12 meters vs. Rehab improved by +8 meters (adjusted difference 4 meters; 95% CI, -18 to 26; P = .72)

- **Patient-reported outcomes (quality of life, anxiety, depression, fatigue):** No significant between-group differences at any time point.

**Adherence:** In the Prehab group, adherence to the exercise program (attending ≥ 70% of prescribed sessions) was approximately 75%. Nutritional supplement adherence was ~80%. Psychological session attendance was ~70%. Adherence in the Rehab group (postoperative only) was similar.

**Mortality:** One patient in the Prehab group died within 30 days (1.8%) vs. two in the Rehab group (3.6%); this difference was not statistically significant.

The primary outcome showed a non-significant reduction in the Comprehensive Complications Index of 3.2 points. To put this in context:

A CCI of 0 means no complications. A CCI of 20.9 (Prehab group average) corresponds roughly to a single grade II complication (e.g., a wound infection requiring antibiotics) or two minor grade I complications (e.g., a mild fever and temporary nausea).

A difference of 3.2 points is small. For comparison, a single additional grade I complication (e.g., a urinary tract infection treated with oral antibiotics) adds about 8–10 points to the CCI. So the observed difference is less than half the impact of one minor complication.

The 95% confidence interval (-11.8 to 5.3) means the true effect could range from a moderate reduction in complications (11.8 points lower, equivalent to preventing one moderate complication) to a small increase in complications (5.3 points higher). The study cannot rule out either possibility.

For the secondary outcomes, the absolute risk reduction for any complication was 5.5% (54.5% vs. 60.0%), meaning you would need to treat about 18 patients with prehabilitation to prevent one additional patient from having any complication. For severe complications, the absolute risk reduction was 1.8% (number needed to treat = 56). Both are non-significant.

**Acknowledged by authors:**

The study was underpowered for the primary outcome due to a larger-than-expected variability in CCI scores (SD ~30 vs. assumed 25).

The single-blind design could not blind patients or coaches, introducing potential bias in patient-reported outcomes and adherence.

The Rehab group received the same program postoperatively, which may have attenuated differences. A no-intervention control might have shown a benefit for prehabilitation.

The study was conducted at two academic hospitals with established enhanced recovery pathways, which may limit generalizability to centers without such pathways.

Frailty was assessed using the Fried Frailty Index, which may not capture all aspects of frailty relevant to surgical outcomes.

**Critical reader notes:**

Adherence was only ~70–80%, meaning about one-quarter of patients did not receive the full intended dose. This dilutes the intervention effect and makes it harder to detect a true benefit.

The 4-week prehabilitation period may be too short to produce meaningful physiological changes in frail elderly patients. Muscle hypertrophy, for example, typically requires 8–12 weeks of consistent training.

The multimodal program was complex and resource-intensive. It is unclear whether any single component (e.g., protein supplementation alone) might have been sufficient or whether the combination was necessary.

The study excluded patients who were not frail, so results cannot be generalized to non-frail patients, who might respond differently.

The primary outcome (CCI) is a composite score that may be less intuitive than simple complication rates. However, it is more sensitive and is recommended for surgical trials.

Industry funding: The study was funded by the Canadian Institutes of Health Research (public funding), so no direct industry bias. However, the protein supplements were provided by a commercial company (Ensure, Abbott Nutrition), which could introduce indirect bias, though this is unlikely to affect the primary outcome.

For someone running their own n=1 experiment (e.g., preparing for elective surgery or optimizing recovery from a major health event):

### What to test

**Intervention:** A multimodal prehabilitation program consisting of:

- **Exercise:** 30–45 minutes of moderate aerobic exercise (e.g., brisk walking, stationary cycling) 5 days per week, plus resistance training (e.g., bodyweight squats, resistance bands, light weights) 2–3 days per week, plus flexibility/stretching 5–7 days per week.

- **Nutrition:** Daily protein supplementation (e.g., 20–30 grams of whey or plant-based protein powder) plus a high-protein diet (1.2–1.5 g protein per kg body weight per day). Also, ensure adequate caloric intake to avoid weight loss.

- **Psychological support:** Daily relaxation exercises (e.g., 10–15 minutes of deep breathing, progressive muscle relaxation, or guided imagery) and cognitive