Introduction
Orthopedic oncology is one of the newest subspecialties in orthopedics that specializes in the management of musculoskeletal tumors, which are slowly increasing globally. The great variability of complexity and duration of oncologic orthopedic surgeries is such that there is no guide that can universalize the management for all patients. Surgery can range from short duration with limited bleeding to more demanding procedures such as sacrectomies or hemipelvectomies that require more complex management. Many procedures often require significant neurovascular dissection, removal of bone and/or significant muscle, replacement of large segments of bone and adjacent joints that may also require significant cement boluses for fixation, and free and rotational flaps. A clear understanding of what surgery implies allows proper positioning, airway management, and postoperative planning. –
Patients undergoing surgery to remove bone tumors have frequently received diverse preoperative medical treatments such as chemotherapy, radiotherapy, or a combination. The possible side effects of these agents are diverse. For example, doxorubicin, which is commonly used in bone chemotherapy, can cause dilated cardiomyopathy and arrhythmias. Bleomycin can lead to pulmonary fibrosis, and vincristine can contribute to peripheral neuropathy. In addition, patients who have undergone chemotherapy or radiotherapy may have significant anemia and thrombocytopenia, which could require transfusions of red blood cells or platelets. Obtaining adequate intravenous (IV) access and invasive monitors in preparation for resuscitation with fluids and possible transfusions can be a secondary challenge in ongoing cancer treatments. If the possibility of large blood loss due to a highly vascularized tumor is expected, preoperative tumor embolization may be considered. ,
Oncoanesthesia and Some of the Crucial Steps for Better Perioperative Outcomes
Preoperative Evaluation
Patients with cancer, in addition to having many comorbidities, might have received previous treatments of chemotherapy or radiotherapy; therefore the surgical team must be aware of the side effects of these oncologic treatments on different body organs. In addition, it is crucial to be aware of the natural evolution of tumors. Comorbidities, such as diabetes, cardiovascular, pulmonary, cerebrovascular, and renal diseases, should be thoroughly investigated. The presence of previous chronic pain, use of anticoagulants or antiplatelet agents, and history of thromboembolic disease should be identified. In patients who received neoadjuvant therapies, a key question is whether they have experienced a decrease in their tolerance to exercise before and after treatment.
Physical Examination
The surgical and anesthesiology team must pay special attention to the features/findings detected during examination that may complicate the surgery. For example, patients with malignancy in the head and neck area must undergo rigorous examination of the airway. Tumors can cause airway obstruction and injury to the recurrent laryngeal nerve, as well as vascular obstruction, resulting in superior vena cava syndrome, which can be aggravated with the use of positive pressure ventilation. In addition, it is important to consider that these patients may have received neoadjuvant radiotherapy and therefore undergone anatomic changes.
Selecting an Anesthetic Technique
There is increasing evidence (mostly retrospective and in vitro) that anesthesiology techniques might influence the outcomes of oncologic procedures. Laboratory data show some signal toward positive or negative effects depending on the drug or intervention studied. Although there are many variables to consider in the choice of anesthetic technique, perhaps the most important in the cancer patient are anesthetic maintenance (total intravenous anesthesia [TIVA] with propofol or AGB with inhaled agents) and the use of regional anesthesia.
Anesthetic Maintenance
Different research protocols have concluded that volatile anesthetics induce apoptosis of natural killer cells (NK) and T lymphocytes, which might potentially lead to a deleterious influence on tumor metastases. These agents increase angiogenesis by releasing hypoxia-inducible factor 1α (HIF-1α). The increase in HIF correlates directly with the severity of the tumor, the risk of metastasis, and the presence of chemoresistance. Propofol can be an alternative. It exerts its protective effects through several mechanisms, including antiinflammatory effects, type 2 cyclooxygenase (COX-2) inhibition and prostaglandin E2 (PGE2) reduction, increased antitumor immunity, and preservation of NK cell function. Propofol may also cause inhibition of matrix metalloproteinase (MMP), molecules that promote tumor invasion and dissemination. A retrospective cohort in the UK reported a 5% increase in overall survival in the 5-year follow up among >2600 patients in those who received propofol as an anesthetic technique compared to an inhaled technique. In a retrospective analysis, patients undergoing surgery for breast, colon, and rectal cancer found that after adjustment for all variables, the differences were not statistically significant. In another study in patients undergoing modified radical mastectomy, maintenance with propofol, compared with sevoflurane, reduced the recurrence rate at the 5-year follow up.
Regional Anesthesia
Regional anesthesia is commonly used in orthopedic procedures to prevent or mitigate the response to surgical stress by blocking afferent neural transmission, which prevents the nociceptive stimulus from reaching the central nervous system, while some techniques and anesthetics have been associated with better outcomes. , In two systematic reviews on the impact of different regional techniques (paravertebral block [PVB] and epidural) in patients with breast and gastroesophageal cancer, no difference was found in cancer outcomes compared to other anesthetic techniques.
Orthopedic Cancers
Sarcomas
Regarding mortality due to malignant neoplasms of soft tissue sarcomas (STS), bone and joint sarcomas, people between 30 and 60 years have a mortality rate of 4 deaths per 100,000 inhabitants. STS comprise a group of relatively rare, anatomically and histologically diverse malignancies. They share a common embryologic origin, which arises mainly from tissues derived from mesodermal or ectodermal germ layers. The annual incidence of STS in the United States is approximately 13,130 new cases, with less than 1%–2% of cancer diagnoses.
However, it is estimated that 5000 patients die annually from STS, which is almost 10 times higher than deaths due to testicular cancer. The development of sarcoma after the use of ionizing radiation for the treatment of lymphoma has been reported. Most sarcomas are associated with the use of high rate radiation (87%), and the predominant histologic types include undifferentiated pleomorphic sarcoma, angiosarcoma, and osteosarcoma.
For sarcomas of the extremities, 5-year survival rates remain low, particularly in clinical stages III–IV, where it is 5%–10%.
The WHO classification classifies soft tissue and bone tumors into four categories according to clinical behavior: (1) benign; (2) medium, locally aggressive; (3) medium, rarely with metastases; and (4) malignant (i.e., sarcoma).
Clinical Presentation and Diagnosis
Most patients with STS have a painless mass, although pain is noticeable in the presentation in up to one-third of cases. Physical examination must include an evaluation of the size and mobility of the mass. It is important to note the location of the mass (superficial vs. deep) and nearby neurovascular and bone structures.
Treatment
Chemotherapy and radiation are usually administered before the surgery. These neoadjuvant treatments can reduce the size of the tumor and allow it to be completely removed.
Perfusion of Extremities
A form of hyperthermic intraoperative chemotherapy, using a tumor-containing limb with tumor necrosis factor-alpha (TNF-α), interferon-alpha (IFN-α), and melphalan, has been described. This technique has been used as a neoadjuvant therapy to facilitate tumor resection and as a primary therapy to prevent amputation in patients with STS of unresectable limbs. Regarding side effects, chronic edema is the most common long-term complication.
Bone Tumors
Malignant bone tumors account for a small percentage of cancers nationwide and are much less common than soft tissue malignancies. The most common primary malignant bone tumors, osteosarcoma and Ewing sarcoma, present in childhood. Chondrosarcoma occurs most often in older adults. Rare tumors such as chordoma and adamantinoma have anatomic predilections for the sacrum and tibia, respectively. The main symptom of a patient with a malignant bone tumor is pain, which often occurs at rest or at night. There are also characteristic findings on physical examination such as swelling or decreased range of motion of the joints. Patients with possible malignancy require complete staging to determine the extent of the disease and a well-planned biopsy for an accurate diagnosis. Biopsy may be an image-guided needle biopsy or open incisional biopsy. It is important to know the specific characteristics of the tumor and the treatment options for osteosarcoma, Ewing sarcoma, chondrosarcoma, malignant fibrous histiocytoma, chordoma, and adamantinoma. Patients with resectable osteosarcoma and Ewing sarcoma are treated with chemotherapy followed by surgical resection. Secondary sarcomas can occur in previously benign bone lesions and require aggressive treatment. There are specific techniques for the resection of malignant bone tumors of the upper and lower extremities, pelvis, and spine. Reconstruction options include the use of vascularized allografts, megaprostheses, and autografts. There has been a trend toward more prosthetic reconstructions due to early complications with allografts. The care of patients with primary malignant bone tumors requires a multidisciplinary approach to treatment.
Regional Anesthesia and Cancer
It is important to avoid a prooncogenic environment in patients with an already altered response toward their environment and, consequently, to surgical stimuli. Surgical tumor resection remains the main technique for the treatment of most types of cancer. The anesthesiologist’s role is to select appropriate techniques to reduce the release of proinflammatory cytokines in the perioperative period. Regional anesthesia may have a modest role, but there is currently no concrete clinical evidence to support this hypothesis. A well-applied peripheral blockade can positively influence early postoperative outcomes, such as better analgesia and better quality of recovery in patients with cancer.
Combining peripheral regional techniques with general anesthesia may reduce the use of IV opioid consumption, which may facilitate earlier postoperative recovery.
Anesthetic Agents and Impact on the Immune System
Volatile Anesthetics
The available evidence is limited, and most of it comes from experimental studies. However, there is a signal toward the suppressive effect of volatile anesthetics on the immune system of patients with cancer.
Sevoflurane induces apoptosis of T lymphocytes, increases HIF-1α, increases plasma levels of protumorigenic cytokines (interleukin [IL]-1β, TNF-α, and IL-6) and MMPs that have been associated with modifications in the oncologic outcomes. It also decreases the amount and activity of NK cells.
In a small retrospective analysis, progression-free survival time for women with ovarian cancer was longer for women who received desflurane than for those who received sevoflurane anesthesia. However, such retrospective analyses are inherently limited and do not warrant a change in practice.
Intravenous Anesthetics
By contrast, propofol inhibits HIF-1α and inhibits the production of prostanoids by suppressing the activity of COX-2, induces apoptosis, and suppresses proliferation, cell adhesion, migration, and angiogenesis in various cancer cell lines. Theoretically, these laboratory model characteristics may be beneficial to patients with osteosarcoma and other cancers.
Recent experimental data have shown a reduction of IL-6 up to 6 h after surgery, inhibition of nuclear factor kappa B (NF-κB), inhibition of neutrophil activation, and proinflammatory regulation of synthetase oxide and cyclooxygenase.
Regarding the use of alpha-2 agonists, mainly dexmedetomidine, a potential beneficial effect was initially associated with a reduction in the use of volatile opioids and anesthetics, in addition to immunoprotective and antiinflammatory properties. However, recent data suggest that dexmedetomidine may promote tumor growth and stimulate prometastatic modification of the tumor microenvironment.
Opioids
The impact of opioid use on patients with cancer is controversial. Morphine suppresses both the activity of NK cells and the differentiation of T lymphocytes, promotes lymphocyte apoptosis, and decreases the expression of Toll-like receptor 4 (TLR4). Fentanyl and sufentanyl have similar effects decreasing NK cell activity; however, they increase the amount of regulatory T cells. Sufentanyl apparently also inhibits leukocyte migration, while alfentanil decreases the activity of NK cells.
It is important to emphasize that the mu opioid receptor (MOR) is expressed in various tumor and nontumor cell types, and despite the predominantly immunosuppressive nature of opioids, it is important to note that their effects depend on the type of opioid administered, total dose, and additional conditions.
Opioids also have immunomodulatory properties; for example, morphine induces changes in macrophages from M1 to M2. This effect is consistent with the increase in COX-2 expression in macrophages.
In murine in vivo models, continuous use of morphine compared to its intermittent use is more likely to inhibit tumor growth and metastasis.
Based on the evidence proposed, it is possible to infer that not only the type of opioid used, but also the dose may influence their effect on cancer cell biology. However, at present, there is no clinical evidence that warrants any change in practice. Therefore cancer patients for whom opioids are indicated for postoperative analgesia should receive them without hesitation.
Nonsteroidal Antiinflammatory Drugs
Few studies have focused on the perioperative effects of nonsteroidal antiinflammatory drug (NSAID) use in terms of possible oncologic effects.
Choi et al. concluded that the use of ketorolac in patients with lung cancer resulted in better disease-free survival, while Forget et al. found that it was independently associated with a lower risk of metastasis and greater survival. Both are inherently limited retrospective studies.
Local Anesthetics
Recent studies have reported that both lidocaine and ropivacaine can inhibit the growth, invasion, and migration of tumor cells in vitro. In addition to inducing apoptosis, , antiinflammatory properties were evident with IV lidocaine use.
In vitro studies of tongue cancer cells found that amide local anesthetics inhibited cancer cell migration by epidermal growth factor receptor (EGFR) inhibition. Other studies involving the use of ropivacaine and bupivacaine reported beneficial effects in specific cancer cell lines such as breast cancer via DNA demethylation.
Conclusions
The complexity of managing orthopedic oncologic patients requires close multidisciplinary collaboration.
As for all tumor types, no specific anesthetic agent or technique is superior to any other at the present state of knowledge.
References
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Improving Cancer Survival Through Perioperative Attenuation of Adrenergic-Inflammatory Signaling
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Perioperative Care of the Colorectal Cancer Patient
Frailty in the Perioperative Setting for Cancer Patients
Rehabilitation, Palliative Care, and Integrative Medicine Interventions in Cancer
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