DOI: https://doi.org/10.21203/rs.3.rs-708272/v1
Purpose The feasibility and effects of multimodal prehabilitation in patients with advanced ovarian cancer (AOC) undergoing a cytoreductive surgery are unknown. We aimed to evaluate the feasibility of a multimodal prehabilitation program in patients with AOC and its impact on postoperative outcomes.
Methods We prospectively compared 15 patients with AOC stage scheduled to undergo a citorreductive surgery between December 2019 and January 2021 after a multimodal prehabilitation program consisting of supervised exercise training, nutritional optimization and psychological preparation versus a control cohort of 19 patients matched according to clinical and surgical characteristics who underwent surgery without prehabilitation between January 2018 and November 2019. In both groups, the enhanced recovery after surgery guidelines were followed. We analyzed adherence to the program, comprehensive complication index (CCI), hospital length of stay, and time to starting chemotherapy.
Results Overall adherence to the multimodal prehabilitation program was 80%, with 86.7% adherence to exercise training, 100% adherence to nutritional optimization, and 80% adherence to psychological preparation. Median hospital stay was shorter in the prehabilitation cohort [5 days (IQR, 4-6) vs. 7 days (IQR,5-9) in the control cohort, p=0.04]. CCI score in the prehabilitation cohort was 9.3 (SD 12.12) vs. 16.61 (SD 16.89) in the control cohort, p=0.2. Median time to starting chemotherapy was shorter in the prehabilitation cohort compared to control cohort [25 days (IQR, 23-25) vs. 35 days (IQR 28-45), p=0.03].
Conclusion Multimodal prehabilitation is feasible and safe in patients with AOC. This study found significantly shorter hospital stays and time to starting chemotherapy in the multimodal prehabilitation cohort.
The effects of multimodal prehabilitation before surgery for advanced ovarian cancer are unknown.
Multimodal prehabilitation before surgery for advanced ovarian cancer is feasible and safe.
Prehabilitation reduced hospital stay and time to starting chemotherapy in advanced ovarian cancer.
The standard treatment for advanced ovarian cancer (AOC) is complete cytoreductive surgery combined with chemotherapy. Aggressive cytoreductive surgery involves a high risk of serious complications, often resulting in functional deterioration and directly determining postsurgical recovery and survival [1]. Grade III or IV postoperative complications occur over 20% of patients undergoing surgery for AOC, and up to 10% of these result in the death of the patient [1–5]. As a consequence, it might result in delays in chemotherapy, which are directly related to decreased survival [6].
Growing evidence indicates that postoperative organ dysfunction from the surgical stress response is a fundamental cause of postoperative morbidity and mortality [7, 8]. Enhanced Recovery after Surgery (ERAS®) aims to reduce perioperative morbidity and decrease the length of hospital stay without increasing readmission rates [9, 10], but ERAS®measures mainly focus on perioperative and postoperative care, disregarding the assessment of presurgical risk factors.
Recent trials have shown that multimodal prehabilitation programs including extensive preoperative evaluation and nutritional and psychological strategies in addition to physical intervention have a positive impact on postoperative functional outcomes in other, non-gynecological major abdominal surgeries [10–13]. To our knowledge, strong evidence for the beneficial effects of prehabilitation in gynecological interventions is lacking [14]; the only published information available about prehabilitation programs in patients with gynecologic cancer comes from a single case report [15].
Thus, we aimed to evaluate the feasibility and effectiveness of a multimodal prehabilitation program in patients undergoing surgery for AOC.
This prospective study compared patients who underwent surgery for AOC (FIGO stage IIIC or IV) at a university hospital between December 2019 and January 2021 after a multimodal prehabilitation program against a historical cohort of controls matched according to clinical and surgical characteristics who underwent surgery at the same hospital between January 2018 and November 2019 without prehabilitation.
The prehabilitation group included: 1) patients with AOC who underwent primary debulking surgery or interval surgery after 3 or- 4 cycles of chemotherapy; 2) recurrent ovarian cancer who underwent secondary and/or cytoreductive surgery; 3) patients scheduled for a multimodal prehabilitation program at least 2 weeks before surgery; 4) Patients classified as Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. The exclusion criteria were as follows: 1) Unstable respiratory or heart disease and 2)3) locomotor or cognitive limitations.
Our institution’s ethics committee (HCB/2020/0317) approved the study, and all in the pehabilitation cohort provided written informed consent; the ethics committee waived the need for consent in the control group because the study had no repercussions in their care and the confidentiality of their data was assured.
In addition to standard care based on ERAS® protocols [2], patients in the prehabilitation cohort underwent a multimodal prehabilitation program aimed at improving physical activity, nutrition, and psychological readiness. We performed a baseline, pre-operative and 1-month postoperative assessment which included 6 minutes walking capacity (6MWT), Yale Physical Activity Questionnaire, Global leadership initiative on malnutrition criteria and hospital Anxiety and Depression Scale (Fig. 1).
To improve physical activity, patients underwent a supervised exercise program comprising 3 weekly sessions of endurance and resistance training in our hospital gym. Each session comprised high intensity endurance training on a cycloergometer or treadmill and strength training. Endurance training consisted of a 5-minute warm-up followed by 30 minutes of high-intensity interval training and a 5-minute cool-down; workload was set according to the patient’s tolerance using the Borg Rating of Perceived Exertion scale [3]. Strength training consisted of 3 sets of 10 to 15 repetitions of three exercises: horizontal row, chest press, and quadriceps bench. Moreover, patients received a fitness tracker. Physical activity goals were established during a motivational interview on the first day of the prehabilitation program and adjusted weekly according to the patient’s attainment. To prevent possible postoperative respiratory complications, patients underwent respiratory physiotherapy with a volume-oriented incentive spirometer.
To improve nutritional status, a registered dietitian elaborated a nutritional intervention plan after assessing patients’ initial status with the global leadership initiative on malnutrition criteria [4] and bioimpedance analysis. The plan aimed to ensure patients’ caloric and protein requirements were met through diet and supplementation with whey protein isolate (Fresenius©) when necessary, targeting ingestion of 1.6–2 g protein/kg body weight/day to stimulate muscle mass synthesis. Before surgery, patients were administered an immunomodulatory formula with specific nutrients such as arginine, omega-3 fatty acids, glutamine and antioxidants.
A clinical psychologist used the Hospital Anxiety and Depression Scale [5] to assess patients’ psychological state, referring patients with comorbid psychopathology to a specialized service, and personal interviews to assess coping strategies and motivation to engage in the activity and nutritional programs. To boost patient motivation and learn coping strategies to manage symptoms of anxiety and depression, patients attended cognitive behavioral group sessions. During the COVID-19 outbreak, these sessions were replaced with individual online sessions. These sessions were complemented with psychoeducational material and audio guides using cell phone applications.
Adherence to the multimodal prehabilitation program was deemed satisfactory when the patient completed ≥ 6 exercise training sessions or ≥ 75% of scheduled exercise training sessions, fulfilled ≥ 75% of protein supplementation intake and immunomodulatory formula before surgery, and attended ≥ 1 session with the psychologist.
This cohort followed preoperative measures and enhanced recovery protocols [2] established in our hospital.
All surgeries were performed by experienced gynecologic oncologists, who used the Aletti score to estimate surgical complexity [6] and the European Society of Gynaecological Oncology’s Ovarian Cancer Operative Report to calculate the peritoneal cancer index (PCI). Postoperative complications were recorded, assessed with the Clavien-Dindo classification [7], and summarized with the comprehensive complication index [8]. Length of hospital stay and complications within 30 days after surgery were also recorded. Time to starting chemotherapy was defined as the period from the day of surgery to the first chemotherapy session.
Results are presented as mean (SD) or median (IQR) for quantitative variables based on the distribution of the data. Categorical variables were represented using relative frequencies (percentages). To compare continuous variables, we used Student’s t-test or the Mann-Whitney U, as appropriate. To compare categorical variables, we used the chi-square test or Fisher’s exact test, as appropriate. We also used univariate regression analysis to compare characteristics and oncological outcomes of patients with advanced ovarian cancer treated with or without multimodal prehabilitation. All tests were 2-tailed. Imputation of missing values was not performed. The STATA statistical program (STATA v.15.0; StataCorp LLC, College Station, TX) was used for data analysis.
We included a total of 34 patients, 15 in the prehabilitation cohort and 19 in the control cohort. Initially, of the 17 patients assessed for eligibility to receive prehabilitation, 1 declined participation and another did not have enough time to perform prehabilitation. There were no lost to follow-up in the evaluation 1 month after the intervention.
The two cohorts were similar with respect to age, PCI, Aletti score, and other baseline surgical, clinical, and pathology characteristics, but preoperative prealbumin levels were higher in the prehabilitation cohort (0.235 [0.214–0.316] g/L vs. 0.1805 [0.130–0.230] g/L in controls, p < 0.01) (Table 1).
|
Characteristics |
Prehabilitation cohort n = 15 |
Control cohort n = 19 |
P-value |
|---|---|---|---|
|
Age (years), median [IQR] |
55 [52–69] |
60 [52–72] |
0.50 |
|
Body mass index (kg/m2), median [IQR] |
25 [23–26] |
24 [24–26] |
0.36 |
|
Charlson Comorbidity Index, median [IQR] |
4 [3–5] |
4 [3–6] |
0.80 |
|
ECOG, n (%) 0 1 |
1 0 5 |
6 13 |
0.08 |
|
CA 125, median [IQR] |
30 [16–166] |
76 [30–585] |
0.09 |
|
Preoperative albumin (g/L), median [IQR] |
44 [43–46] |
44 [36–46] |
0.3 |
|
Preoperative prealbumin (g/L), median [IQR] |
0.235 [0.214–0.316] |
0.1805 [0.13–0.23] |
0.007 |
|
FIGO staging, N (%) III B III C IV A IV B |
1 (6.7) 5 (33.4) 4 (26.7) 5 (33.4) |
0 (0) 12 (63.2) 0 (0) 7 (36.8) |
0.029 |
|
Histology, n (%) Low-grade serous carcinoma High-grade serous carcinoma Endometrioid carcinoma Granulosa cell tumor |
1 (6.7) 12 (80) 1 (6.7) 1(6.7) |
2 (10.5) 16 (84.2) 1 (5.3) 0 (0) |
0.87 |
|
Duration of surgery (minutes), median [IQR] |
320 [255–280] |
310[270 − 260] |
0.40 |
|
PCI, median [IQR] |
10 [8–14] |
10 [8–14] |
0.97 |
|
Type of surgery, n (%) Primary cytoreduction Interval surgery Secondary and tertiary cytoreduction |
1(6.7) 11(73.3) 3(0.2) |
7(36.8) 11(57.9) 1(5.2) |
0.21 |
|
Procedure, n (%) Hysterectomy + bilateral salpingo-oophorectomy |
11 (73.3) |
18 (94.73) |
0.14 |
|
Pelvic peritonectomy |
6 (40) |
5 (26.31) |
0.475 |
|
Intestinal resection Colorectal resection Large bowel resection Small bowel resection Appendectomy Radical omentectomy Partial hepatectomy Splenectomy Diaphragmatic stripping HIPEC Debulking of pelvic/paraaortic lymph nodes |
7 (46.66) 5 3 3 4 (26.67) 12 (80) 1 (6.67) 2 (13.3) 7 (46.67) 1 (7.14) 10 (66.67) |
10 (52.63) 3 5 5 6 (31.58) 17 (89.47) 0 (0) 1 (5.26) 4 (21.05) 1 (5.26) 14 (77.78) |
1.00 1.00 1.00 0.69 1.00 0.63 0.44 0.57 0.15 1.00 0.69 |
|
Aletti Complexity Score, median [IQR] |
6 [4–8] |
7 [4–8] |
0.51 |
|
Residual disease, n (%) R0 R1 R2 |
13 (86.) 1 (6.7) 1 (6.7) |
19 (100) 0 (0) 0 (0) |
0.18 |
| IQR: Interquartile range; ECOG: Eastern Cooperative Oncology Group; PCI: peritoneal cancer index; HIPEC: hyperthermic intraperitoneal chemotherapy; CA = cancer antigen | |||
Adherence to the multimodal prehabilitation program was satisfactory in 12 (80%) patients. Adherence to physical training was satisfactory in 13 (86.7%) patients; logistic issues prevented 2 patients from achieving satisfactory adherence. The median duration of the prehabilitation program was 2 weeks (IQR, 2–3), and patients attended a median of 6 (IQR, 4–8) supervised exercise training sessions. Median adherence per person to the training sessions was 83% (IQR, 60–100). Three patients reported mild dizziness during sessions that did not prevent them from continuing the session. Regarding the nutritional program, adherence to protein supplementation and immunomodulatory formula was ≥ 75% in all patients. (Table 2). Adherence to psychological sessions was satisfactory in 12 (80%) patients.
|
Characteristics |
Prehabilitation cohort |
|---|---|
|
Duration of program (weeks), median weeks [IQR] |
2 [2–3] |
|
Number of gym sessions, median [IQR] |
6 [4–8] |
|
Adherence to gym sessions: Patients completing > 2 sessions or > 75% of scheduled sessions, n (%) Adherence (%), median [IQR] |
13 [86.6] 83 [60–100] |
|
Adverse effects, n (%) Mild dizziness |
3/15 [20] 3/15 (20) |
|
Adherence to nutrition intervention > 75%, n (%) |
15 (100) |
|
Adherence to psychological intervention ≥ 1 session, n (%) |
12 (80) |
The proportion of patients who required interval cytoreductive surgery was not significantly different between groups (73.3% in the prehabilitation cohort vs. 57.9% in the control cohort, p = 0.21). Median Aletti scores were similar (p = 0.51) in the two groups. ICU stays were shorter, but the difference was not significant between groups (p = 0.88). Postoperative complications occurred in 6 (40%) patients in the prehabilitation cohort and in 12 (63.15%) patients in the control cohort (p = 0.30); Clavien-Dindo grade III complications were observed in 5 (26.3%) patients in the control cohort, but in none of those in the prehabilitation cohort. Mean comprehensive complication index scores were not significantly different (9.3 (SD 12.12) in the prehabilitation cohort vs. 16.61 (SD 16.89) in the control cohort, p = 0.2). Median length of hospital stay was shorter in the prehabilitation cohort (5 days (IQR, 4–6) vs. 7 days (IQR,5–9) in the control cohort, p = 0.04); Median time to starting chemotherapy was shorter in the prehabilitation cohort (25 days (IQR, 23–25) vs. 35 days (IQR 28–45) in the control cohort, p = 0.03). Table 3 reports all surgical variables and outcomes.
|
Characteristics |
Prehabilitation cohort n = 15 |
Control cohort n = 19 |
P-value |
|---|---|---|---|
|
Hospital stay (days), median [IQR] |
5 [4–6] |
7 [5–9] |
0.041 |
|
Intensive care unit stay, days (%) 0 1 2 3 |
9 (60) 5 (33.3) 1 (6.7) 0 (0) |
9 (47.4) 6 (31.6) 3 (15.8) 1 (5.3) |
0.88 |
|
Intraoperative complications, n (%) Intestinal injury Vascular injury Urological injury Nerve injury Need for blood transfusion |
1 (6.7) 0 (0) 0 (0) 0 (0) 1 (6.7) |
1 (5.3) 0 (0) 0 (0) 0 (0) 5 (26.3) |
0.40 |
|
CCI, median [IQR] Mean, SD |
0 [0–20,9) 9,33 (12,1) |
8,66 [0–33,5] 16,62 (16,9) |
0.36 0.20 0,08 |
|
Clavien-Dindo classification < 30 days, median [IQR] |
|||
|
Patients with no complications Patients with ≥ 1 complications |
9 (60) 6 (40) |
7 (36.84) 12 (63.15) |
|
|
I II III a III b IV a IV b V |
4(40) 6(60) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) |
4 (23.5) 8 (47) 2 (11.8) 2 (11.8) 1 (5.9) 0 (0) 0 (0) |
0.30 |
|
Major complications (Clavien-Dindo ≥ III), n (%) |
|||
|
No Yes |
15 (100) 0 (0) |
14 (73.7) 5 (26.3) |
0.053 |
|
Type of complications, n (%) Paralytic ileus / intestinal obstruction Cardiovascular complications Pulmonary complications/DVT/PE Anastomotic leakage /peritonitis Infection/postsurgical abscess Postsurgical bleeding/ need for transfusion Lymphocele/ lymphatic complications |
4 (40) 0(0) 0(0) 0(0) 3(30) 2(20) 0(0) |
1 (5.3) 1(5.3) 0(0) 0(0) 5(26.3) 9(47.3) 3(15.8) |
0.714 |
|
Time to starting chemotherapy (days), median [IQR] |
25 [23–35] |
35 [28–45] |
0.03 |
| DVT: deep vein thrombosis; PE: pulmonary embolism (PE); CCI: comprehensive complication index | |||
In this pilot study, a multimodal prehabilitation program consisting of moderate-intensity physical exercise together with nutritional supplementation and psychological support measures before cytoreductive surgery yielded promising results. The program was feasible (adherence was high) and safe (no major adverse effects occurred). Hospital stay and time to starting chemotherapy were lower in the prehabilitation cohort than in the matched cohort of historical controls, although both groups received perioperative care in accordance with ERAS guidelines.
Because patients with AOC who are candidates for cytoreductive surgery often present considerable cognitive and physical deterioration in the context of malnourishment [9], a high-intensity program of interval training in such fragile patients in a short timeframe before surgery might be considered unfeasible. However, we found high adherence to the supervised exercise sessions, and we observed no adverse effects that would prevent continuing the training exercises. Supervised structured exercises encourage patient adherence despite their poor baseline functional state. Although some studies in patients undergoing other abdominal surgeries used easier alternatives such as walking-based interventions performed at home, these approaches depend on self-reporting, so adherence rates may be unreliable [10–11]
Whether short high-intensity exercise programs can bring about sufficient improvement is controversial. The duration of prehabilitation in non-gynecological major abdominal surgeries ranges from 2 to 6 weeks [12]. In patients with AOC, it is important to complete the prehabilitation program in the shortest period of time possible to avoid tumor progression and detrimental effects on oncologic outcomes [13–14]. However, most patients undergo neoadjuvant chemotherapy, making it possible to plan and carry out an appropriate program within the optimal timeframe. In a systematic review analyzing the effects of a preintervention exercise program in patients undergoing abdominal surgery, Moran et al. [10] concluded that prehabilitation in patients treated with neoadjuvant chemotherapy is safe and can increase aerobic capacity before surgery. In line with these results, in our study, most patients were receiving neoadjuvant chemotherapy, and adherence to the exercise program was very high.
Adherence to the second component of our multimodal prehabilitation program, the ingestion of preoperative nutritional complements and immunomodulatory preparations, was excellent. A prospective randomized study in non-malnourished patients undergoing surgery for abdominal cancer found that nutritional supplementation for 14 days before surgery significantly reduced the number and severity of postoperative complications [15], and another study showed that immune-enhancing proteins reduce complication rates [16]. In our study, patients in the prehabilitation cohort had significantly better levels of prealbumin than the control cohort.
Adherence to the third component of our multimodal prehabilitation program, psychological support, was also high. No firm evidence is available about the effectiveness of employing anxiety-reduction strategies before surgery. A Cochrane review found only low-quality evidence supporting psychological preparation for postoperative pain, behavioral recovery, and length of stay [17]. Thus, we can only speculate that these methods helped patients in our program to deal with the stressful preoperative period and reinforced adherence to the physical and nutritional interventions.
There is no consensus about how to measure the potential benefits of prehabilitation programs [18–20]. To analyze postoperative complications, we used the comprehensive complication index to report and summarize patients’ overall morbidity after surgery. To our knowledge, our is the first study to use this more robust approach. The rate of complications in our prehabilitation cohort was not significantly different from the rate observed in the control cohort, probably due to the small number of patients in this pilot study. In a blinded randomized controlled trial to assess the impact of a prehabilitation intervention on perioperative complications in high-risk patients undergoing major abdominal surgery, Barberan-Garcia et al. [21] found a lower rate of postoperative complications (31% vs. 62% in controls; p = 0.001), demonstrating the intervention’s protective role against postoperative complications.
In our study, hospital length of stay was significantly lower in the prehabilitation cohort, although both groups received perioperative care in accordance with ERAS guidelines. Hospital length of stay seems a good indicator of the effect of prehabilitation, because it reflects the extent to which patients have recovered baseline physical functioning; moreover, shortened stays likely result in lower hospital costs. Nevertheless, other studies have reported discrepant results regarding the effects of prehabilitation on hospital stay [12, 22, 23]; these discrepancies might be explained by multiple factors such as the heterogeneity of operative procedures and postoperative care protocols. Most reports fail to mention whether ERAS care pathways were used for postoperative care. Finally, non-medical reasons could influence when patients are discharged from the hospital. Future studies should use standardized postoperative care pathways to enable comparison among studies.
We also analyzed the effect of prehabilitation on the time to starting chemotherapy. Combined cytoreductive surgery with platinum and taxane-based chemotherapy is the standard of care in AOC. We found the time to starting chemotherapy was significantly lower in the prehabilitation cohort than in the control cohort. Shorter time to starting chemotherapy could directly improve patients’ prognosis of the patient since delays in initiating systemic therapy are associated with decreased survival in patients with AOC [13].
One major strength of our study is our center’s specialized coordinated multidisciplinary group that has accumulated extensive experience in prehabilitation and achieved encouraging results in non-oncological gynecologic surgery. Moreover, patients diagnosed with AOC stand to benefit more from prehabilitation than other groups of patients because they are at high risk of postoperative complications and functional decline after surgery. We designed a multimodal prehabilitation program to maximize the impact on functional outcomes, as multimodal programs are more effective than single-mode prehabilitation interventions [24]. Finally, to minimize differences in perioperative care and to make our results easier to compare with future studies, we used ERAS® pathways for both cohorts.
Some limitations of our study are important. This was a pilot study including a low number of patients at a single institution, so caution is warranted in extrapolating our results to other contexts. The non-randomized study design is a major limitation, although control patients were matched for important demographic, clinical, and surgical variables, and the same surgical and postoperative protocols were followed in both cohorts, reducing possible biases due to differences in treatment or follow-up.
This preliminary study shows that multimodal prehabilitation is feasible, safe, and effective in patients with AOC. This approach needs to be evaluated further in larger, randomized trials involving multiple centers. Along these lines, our encouraging results have led us to design a multicenter randomized controlled trial, SOPHIE (Surgery in Ovarian cancer with Pre-Habilitation InERAS environment, ClinicalTrials.gov, number NCT 04862325), which will start recruiting patients in 2021.
The multimodal prehabilitation program described here was feasible in patients with AOC and resulted in significantly shorter hospital stay and time to starting chemotherapy.
Author contributions
The authors state that each of the authors have provided substantial contribution and are in agreement with all aspects of the final manuscript.
Conflict of interests
The authors have no conflicts to declare
Funding support
None to be declared.
Ethical approval
This article does not contain any studies with human participants performed by any of the authors.
Precis
Good adherence and promising results in this pilot study of a multimodal prehabilitation program in patients with advanced ovarian cancer show it is feasible in this vulnerable population.
Contribution statement
B Diaz-Feijoo: Project development, data collection, data analysis, investigation, project administration and manuscript writing.
N Agustí: Project development, data collection, data analysis, project administration and manuscript writing.
Raquel Sebia and Antonio López: Physical activity program conceptualization and project supervision
Marina Siso: Nutritional program conceptualitzation and supervision.
Aureli Torné, Graciela Martinez-Palli and Mª José Arguís: Project development and data collection.
All authors provided critical feedback and helped shape the research, analysis and manuscript.