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.
Results in the Context of Published Literature
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].
Strengths and Weaknesses
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.
Implications for Practice and Future Research
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.