Research in Perioperative Care of the Cancer Patient: Opportunities and Challenges

Basic Science and Translational Studies

Since the early 1990s there has been a rapid increase in in vitro and in vivo animal investigations evaluating the effect of single or combined perioperative interventions on tumorigenesis and metastasis. Most of those preclinical studies indicate that surgical stress, volatile anesthetics, and opioids can mediate cancer progression by (1) acting on signaling mechanisms that promote cell survival, proliferation, epithelial-mesenchymal transition, and metastatic cell behaviors; (2) inducing inflammation and suppression of the immune response against cancer; (3) triggering angiogenesis; and (4) promoting cancer “stemness.” ^, On the other hand, laboratory studies suggest that a reduction of the surgical stress and inflammatory response via regional anesthesia, infusions of the local anesthetic lidocaine, beta blockers, and antiinflammatory agents, such as nonsteroidal antiinflammatory drugs (NSAIDs), reduce the metastatic burden associated with surgery. ^,

Unfortunately, in the context of perioperative cancer medicine, the translation of experimental animal research into humans has largely failed. For instance, while studies in rodents indicate that minimally invasive surgery reduces cancer progression, well-conducted clinical studies have shown no benefits or the opposite effects in terms of benefits in survival. In addition, significant advances in the areas of genomics, proteomics, and metabolomics have permitted clinicians and clinical researchers to reclassify and treat cancers based on their actionable targets instead of histological subtypes of disease. ^, However, it is still unknown how drugs with multiple potential receptor targets or epigenetic effects, such as anesthetics and some analgesics, can affect oncological outcomes in an era of “precision oncology.”

Clinical Endpoints

When considering randomized controlled trials (RCTs) designed to test the efficacy of perioperative interventions in patients with cancer, improvements in overall survival and quality of life should be considered as the two most important endpoints. ^, While other survival endpoints, such as recurrence-free survival, disease-free survival, progression-free survival, or biochemical-free survival are also commonly used in clinical trials, they do not always correlate well with improvement in overall survival. In other words, when intervention A proves to significantly extend recurrence-free survival time in favor of intervention B, the actual impact on overall survival may not be clinically relevant. ^,

Furthermore, it has to be understood that most clinically available biological surrogate endpoints are poor indicators of the ultimate goal in the treatment of cancer, which is cure (long overall survival). In other terms, a single biomarker or a combination of biomarkers that can be easily measured and/or modulated by perioperative interventions is not always highly predictive of overall survival. As an example, findings from randomized controlled studies in breast cancer patients suggesting that the use of paravertebral block anesthesia caused a significant reduction in biomarkers of inflammation and angiogenesis did not translate in a longer overall survival.

Short- and long-term psychophysical and social recovery after surgery could be considered as endpoints of postoperative quality of life. From the patients’ point of view, recovery is defined as return to “normality.” ^, In the patient with cancer, the definition of recovery can be broadened to their ability to continue with the cancer treatments (adjuvant therapies), such as chemotherapy or radiotherapy. For some malignancies, such as breast cancer, early return to adjuvant therapies is associated with benefits in survival. However, it must be considered that a disconnect between clinical indicators of recovery and patients’ perception of recovery can exist before patients are able to return to their cancer journey, thus patients may still receive adjuvant therapies before achieve psychosocial recovery. We strongly believe that in all patients but specially in those with cancer, postoperative quality of life and recovery should be measured using patient-centered multidimensional tools, in addition to traditional and institutional measures of recovery, such as adequate pain controlled, minimum nausea and vomiting, ambulation, and return to basic physiological functions. ^,

In summary, it is of outmost importance to consider overall survival as the main endpoint in studies testing the efficacy of perioperative interventions in cancer outcomes.