1

Introduction

Pain perception is subjective and often difficult to assess and grade, especially in the immediate postoperative period. Patients may be too sedated to verbalize their level of discomfort, perioperative staff may transfer their personal analgesic expectations to their patients, or patients may downgrade their level of pain because of their culture or limited language proficiency [ ].

In the mid-1990s, pain was declared the fifth vital sign, and as such expected to be aggressively treated [ ]. Opioids were the most commonly used medications during the perioperative period, and the concept of multimodal analgesia was still in its infancy. Several recommendations were issued on how and when to assess pain, suggesting treatment ladders to provide maximum comfort both in the immediate postoperative period and after discharge, independently from the type of surgery [ , ]. The derived practice of prescribing abundant narcotics contributed to the opioid epidemic that has plagued the US for the past 20 years [ ]. As a result, the analgesia pendulum has swung in the opposite direction, giving birth to the culture of “ opioid free ” analgesia [ ]. The aggressive use of regional anesthetic techniques, alone or paired with “cocktails” of adjuvants, have often been used in the attempt to spare surgical patients from the exposure to opioids, with mixed results [ , ].

In contrast to the “ opioid free ” perspective , opioid sparing analgesia attempts to minimize the unwanted side effects associated with opioids, while not avoiding them altogether, but pairing them with adjuvants and regional techniques, tailored to the patient history and clinical indications. This view maintains that the literature will ultimately favor a balanced analgesia approach, bringing the pendulum to its final resting position [ ]. This more nuanced view of opioid analgesia dovetails with an emerging research program that may ultimately inform the clinical use of opioids both in lung cancer surgery and more generally in cancer surgery, i.e., “precision oncoanalgesia.”

2

Current practice: multimodal analgesia in thoracic non cardiac surgery

Thoracic non-cardiac surgery (as well as any surgery affecting the chest) is painful, despite the continuing evolution of both surgical and anesthetic techniques. The incidence of chronic postoperative pain is still high, independent of the surgical technique, with a reported 38% chance of developing chronic and/or neuropathic pain, and concomitant impairment in quality of life [ ]. In the presence of preexisting chronic pain, managing perioperative analgesia becomes even more difficult and usually requires a multidisciplinary approach.

The creation of enhanced recovery after thoracic surgery (ERATS) protocols has changed the way anesthesia is delivered and how analgesia is provided in both in the intra- and immediate post-operative period [ ]. The original World Health Organization (WHO) analgesia ladder has evolved over the past 20 years, replacing opioids with regional anesthesia and adjuvants as foundations, suggesting the use of opioids as rescue [ ]. The popularity of minimally invasive surgery (MIS) has made ERATS protocols feasible, highlighting the importance of multimodal analgesia not only to provide pain control but also to improve discharge rates and lower complications [ ]. The discovery of various chest wall fascial plane nerve blocks, combined with the increased prevalence of MIS over open surgical approaches, has relegated the use of neuraxial analgesia primarily to patients with severe respiratory dysfunction or in the setting of elevated risk of converting MIS to open surgery.

Many fascial plane blocks are currently available to provide analgesia to the chest wall [ ]. The serratus anterior plane block (SAPB) was first described in 2013 by Blanco et al. to provide analgesia to the chest wall after breast surgery [ ]. Its use has significantly increased for MIS thoracic non-cardiac cases, due to its ease of performance and chest coverage of the MIS ports [ ]. As part of a multimodal regimen, SAPB provides adequate analgesia for MIS cases, though the effects are limited in duration. In 2016, Forero et al. [ ] proposed the use of the erector spinae plane (ESP) block as an optimal regional analgesia technique for rib fractures and metastatic pain of the chest wall [ , ], with the use of catheters being described a few years later as a very effective alternative to both epidural and paravertebral catheters [ ]. Large intermittent boluses of either bupivacaine or ropivacaine are commonly employed at different concentrations and volumes, providing better coverage than continuous infusions [ ]. Fascial plane blocks have been enthusiastically adopted despite the paucity of data strongly demonstrating the benefits when compared to neuraxial blocks, mainly because of their ease of performance and the ready availability of ultrasound [ ]. PNBs are highly recommended as a component of multimodal analgesia by the recent updates of the PROSPECT guidelines [ ], and the practice advisory for perioperative pain management of the thoracic surgical patient by the Quality Safety and Leadership working group of the Society of Cardiovascular Anesthesiologists (SCA) [ ].

In the context of ERATS protocols, the current role of opioids is largely relegated to rescue, to be administered primarily after the use of adjuvants or more local anesthetics, claiming their adverse side effects as relative contraindications. Sedation and respiratory depression, with subsequent hypercapnia and/or hypoxemia, and potential reintubation, which would be catastrophic after thoracic surgery, have been quoted as main concerns. Confusion, delirium, nausea/vomiting, constipation and urinary retention are additional downsides limiting opioid use [ ].

To date, the driving force for opioid reduction in lung cancer surgery has been on optimizing analgesia in the context of reducing these side effects. Though still controversial, an evolving body of literature suggests that perioperative opioid use may also affect longer-term oncological outcomes (i.e. recurrence) through pro-tumor activity [ , ]. If true, this finding would provide another rationale for limiting opioid use in lung cancer resection. At the same time, recent studies suggest that the picture is more nuanced, with associations between perioperative opioid exposure and cancer recurrence dependent on cancer type [ , ] and individual patient-specific tumor genomics, both in the lung and other cancer [ ]. If ultimately demonstrated more conclusively, these results could constitute a path forward in the development of “precision oncoanalgesia,” i.e., tailoring analgesia to the cancer patient that includes consideration of cancer type/subtype and underlying tumor genomics.

3

Personalized medicine in the treatment of NSCLC and other thoracic tumors

The role of gene mutations in promoting lung cancer development and its recurrence has been investigated for the past 20 years, leading to significant discoveries that have revolutionized both diagnosis and treatment. Individual patient tumor genomics have guided the choice of specific immunotherapy, checkpoint inhibitors and targeted treatment, both in the early stages of cancer or to prevent recurrence after surgical resection, alone or in combination with radiation [ ].

Genetic mapping of tumor cells via tissue procurement at the time of either tissue biopsy or tumor resection, or a liquid biopsy via venous blood draw, have become widespread practice in many specialized institutions, allowing the creation of local tumor banks and genomic libraries, where specific genotypes are matched with the best treatments and recommendations given by an expert panels of health care providers [ ]. Several genetic aberrations and structural rearrangements, some related to smoking, as well as specific racial and gender differences, have been identified as peculiar for lung cancer and used to target treatment [ ].

Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS mutations have been discovered in several lung and esophageal cancers, and used to target treatment by inhibition of cancer proliferation with good success. Lung cancer is a slow growing tumor, which is silent for most of its life and manifests at a late stage. Adenocarcinoma and squamous cell cancer are the most common forms, affecting all genders. Several factors have been linked to its development, including smoking, environmental factors, and genetic predisposition. The natural history of cancer is to grow and spread to distant areas. This process is facilitated by the local secretion of extracellular vesicles filled with growth factors and mediators that promote the development of distant premetastatic niches [ ] by stimulating angiogenesis, inflammation and stromal remodeling [ ]. Surgery allows resection of macroscopic areas of cancer, and can be curative at the initial stages, especially if negative margins are confirmed. However, tumor cells may escape from the primary site in the blood stream and travel to the distant niches, where they proliferate into metastasis, affecting recurrence and overall long-term survival [ ].

4

Precision oncology – can we learn from the oncologists?

Precision oncology, also known as personalized medicine, aims to provide the right cancer treatment for the right patient at the right dose and time [ ]. At the time of tissue biopsy, part of the specimen is used to sequence the tumor and understand its genetic makeup. The collected information is then compared with a genomic bank and used to build a personalized treatment plan, where one or few drugs are used for the purpose. Patients are followed in time, periodically tested for treatment adjustments, and monitored for recurrence. As good as this approach may seem, it is still not as widespread, due to genetic variability of the same cancer in different patients, which can be also affected by gender, tobacco exposure and geographical location [ , , ]. Cost can be an additional limiting factor for widespread use of precision oncology, suggesting it is precise only for patients who can financially afford treatment. In the US, the costs of molecular technology have decreased substantially in the past two decades, though this may not be the case in the rest of the world, especially in underdeveloped countries [ ].

Despite the current limitations, precision is the future of oncological medicine. Precision oncology is the foundation of a major shift in non-small cell lung cancer (NSCLC) treatment protocols, by focusing on both genetic tumor data and clinical factors, via targeted treatments and immunotherapy. The former halt tumor growth, while the latter modulate the immune response in favor of the host [ ]. In 2017, the National Comprehensive Cancer Network clinical guidelines recommended genomic profiling for patients with NSCLC to guide appropriate targeted treatment against EGFR, ALK, BRAF and ROS1 mutations [ ]. In 2020, KRAS, MET, RET and NTRK were added to the list of recommended mutations as part of a multi-gene sequencing panel, supporting the notion that cancer is not a single entity. Despite evidence of a strong response to targeted treatment, genetic testing is still not done routinely, depriving a significant number of affected individuals of the proper treatment [ ].

5

Precision oncoanalgesia: what is the evidence?

Akin to precision oncology, the goal of “precision oncoanalgesia” is to decrease tumor recurrence and metastasis by optimizing analgesia to a patient’s specific tumor genomics. At the present time, preclinical and clinical data (mostly retrospective) on opioids and cancer outcomes is conflicting or insufficient to provide recommendations for changes in clinical practice [ , ]. A limitation of the existing literature on the topic of anesthesia, analgesia, and oncological outcomes is that studies do not consider one or both of the two fundamental tenets of modern oncology. First, cancer is not one, but many different diseases. Second, as discussed above, a key determinant of the efficacy of specific drugs on outcomes is underlying tumor genomics.

More recent oncoanesthesia studies incorporate one or both aspects of precision oncology. A retrospective study in patients with esophageal cancer found that higher perioperative fentanyl dose was associated with improved oncological outcomes in patients with the squamous subtype specifically [ ]. This study demonstrated that even within a cancer type (esophageal carcinoma), the patient’s subtype could mediate the association between opioid dose and oncological outcome.

Going beyond cancer type/subtype, more recent retrospective studies have incorporated tumor genomics data to suggest that differences therein may modify the dose-response curve between perioperative opioid dose and oncological outcomes, both in magnitude and direction (pro- vs.anti-tumor effect). A retrospective study in early-stage lung adenocarcinoma patients undergoing primary tumor resection demonstrated that increased intraoperative opioid dose was associated with worse overall survival. Pairing the survival data with next-generation tumor sequencing demonstrated that this association was made even worse in patients with tumors harboring a mutation in the CDKN2A oncogene [ ]. Mutations in the CDKN2A oncogene, most frequently homozygous deletions, are common in smoking-associated NSCLC [ ]. By contrast, increased opioid dose was associated with improved recurrence-specific survival in patients with tumor mutations in the WNT or Hippo oncogenic pathways ( Fig. 1 ). The Hippo signaling pathway is highly conserved and functionally related to cell polarity, cell-cell adhesion, and contact inhibition [ ]. Alteration in Hippo was associated with worse two-year disease-free survival in lung adenocarcinoma. The WNT pathway is functionally related to cellular differentiation in early-stage lung cancer [ ].

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