Perioperative Care: Sarcoma
Introduction
Sarcoma is an umbrella term for malignant neoplasms of mesenchymal origin. A wide variety of underlying cell types can become neoplastic, and so these cancers are best understood by division into histologic subtype and anatomic location.
Sarcomas are rare cancers in adulthood, making up less than 1% of all adult malignancies. Approximately 10% are of bony origin and the remainder originate in soft tissues. The occurrence of soft tissue sarcomas is lowest amongst young adults and slowly increases as patients get older, with a dramatic increase in incidence over the age of 50 years. Incidence of bony sarcomas has a bimodal distribution, with a peak in adolescents and young teens, and a second smaller peak in incidence in the elderly. ,
Risk factors for sarcomas are not well understood. There are certain genetic syndromes that predispose to the development of soft tissue and bone sarcomas. Germline mutation in TP53 causing Li–Fraumeni syndrome, loss of function of the NF1 gene causing neurofibromatosis, and RB1 gene-causing retinoblastoma and secondary malignancies are some of the more well-known syndromes. Geographic and race distribution of certain sarcomas, for example, Ewing sarcoma, being more common in Caucasian populations indicate further unidentified genetic links.
Environmental exposures have also been implicated in the development of sarcomas, but studies are small and results conflicting. Radiation exposure is clearly understood to increase the risk of sarcoma, and certain chemicals. However, there is currently insufficient evidence to generate guidelines on limiting exposure.
General Principles
Presentation of the sarcoma patient is determined both by the anatomic location of the tumor and the histologic subtype.
Extremity soft tissue tumors can present with a self-identified mass and symptoms due to invasion or compression of surrounding structures. Patients can complain of worsening pain or pain in a specific neurologic distribution. Persistent unexplained bone pain, recurrent limp, and pathologic fractures are all features of bony sarcomas.
Retroperitoneal tumors tend to present later, with larger tumors, due to the large area for the tumor to expand into before beginning to compress structures and cause symptoms. These patients often describe a prolonged course of vague abdominal symptoms, which are difficult to classify or correlate, prior to undergoing diagnostic scanning.
Diagnosis is usually confirmed by image-guided core biopsy, which permits targeting specific areas of the lesion that are most likely to provide diagnostic tissue. Core needle biopsy is used to reduce the risk of tumor seeding. However, should open incisional biopsy be required, it is advisable that this be done by the team who will perform the definitive resection, as open biopsies have a higher risk of tumor seeding. This incision must be carefully placed to allow later excision.
Retroperitoneal sarcomas provide their own challenges in terms of diagnosis and provision of tissue. The biopsy should be performed by a unit that regularly undertakes such biopsies, as sampling of tissue that is more likely to yield a diagnosis is important (for example, areas of increased density or metabolic activity on scanning). Peritoneal breaches and intraabdominal tumor seeding should be avoided wherever possible. Therefore all core biopsies should be performed via a retroperitoneal approach. Advice should be requested from a high-volume team as to the best method of proceeding. Core biopsy under direct vision can be considered but is at risk of being nondiagnostic and causing vascular injury.
When planning definitive treatment, cross-sectional imaging to assess the relationship of the primary tumor to adjacent organs, as well as to assess for the presence of metastatic disease, is required. Good quality imaging is useful for diagnosis and planning resection. Choice of imaging modality is based on surgeon preference, but CT for central tumors and MRI for skeletal and extremity masses are widely used as the starting point. Functional imaging such as fluorine-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) provides added information about tumor activity and distant disease. , , ,
Histology
The WHO classification of soft tissue tumors includes more than 100 histologic subtypes. Tumor diagnostics are dependent on histologic appearance, patterns of immunohistochemistry (IHC) staining, and molecular pathology. Specific mutations in genes, for example, EWSR1 in Ewing sarcoma, are commonly used to definitively diagnose certain tumors.
In general, sarcomas are named based on the presumed tissue of origin, for example, liposarcomas, leiomyosarcomas, angiosarcoma. This does not apply to all sarcomas and this can cause diagnostic dilemmas. Synovial sarcoma does not originate in synovium but was named because those were the cells that the tumor most closely resembled. IHC patterns are not always definitive. Histologic diagnosis is essential to allow for accurate prognostication and tailored therapy, both surgical and adjuvant. Tumor histology can predict both risk of local recurrence and distant metastasis, and this varies widely across different subtypes. Diagnosis also allows for consideration of added adjuvant or neoadjuvant therapy if benefit has been demonstrated. For example, different treatment strategies will be used when considering a patient with an undifferentiated pleomorphic sarcoma of the extremity, a tumor with a high risk of distant metastases compared to a myxofibrosarcoma, a locally aggressive tumor that has a high rate of local recurrence.
Natural History and Prognosis
The natural history of sarcoma depends on the histologic subtype, with a variety of disease trajectories. In general, the natural history of sarcoma is as a locally aggressive tumor with risk of hematogenous metastasis. Approximately 50% of soft tissue sarcomas (STS) will develop metastatic disease, most commonly in the lungs. Important prognostic factors include histologic grade, subtype, tumor size, pathologic stage, anatomic site, and age. Current American Joint Committee on Cancer (AJCC) staging (8 th edition) also separates extremity and retroperitoneal tumours.
Management
Once histology has been confirmed and the intent of treatment has been assessed as curative or palliative, a management plan can be determined. As with other solid malignancies, the aim of treatment is to minimize the risk of local recurrence and distant metastasis while maximizing the functional outcome. Choice of treatment varies according to histology and lesion location, but many types of sarcoma will receive neoadjuvant chemotherapy or radiotherapy prior to definitive surgical resection.
Neoadjuvant Therapy
The aim of neoadjuvant therapy is to improve local control, assist in lower morbidity resection by decreasing tumor size and viability of margins, and decrease the risk of distant metastases. This therapy can comprise chemotherapy, radiation therapy, or a combination thereof, and varies between institutions according to local preference.
Neoadjuvant Chemotherapy
Most soft tissue regimens are based around use of doxorubicin (anthracycline) with or without added ifosfamide. The key adverse effect of anthracycline-based regimens is the risk of cardiotoxicity. This cardiotoxicity occurs with the first dose and is cumulative. Myelosuppression is also a common side effect of doxorubicin and ifosfamide. Bone sarcomas rely on neoadjuvant chemotherapy prior to surgery, and patients can receive high doses of methotrexate, cisplatin, and doxorubicin. Nephrotoxicity and gastrointestinal side effects are also well documented for methotrexate and cisplatin. Nephrotoxicity can be a particular problem for patients with retroperitoneal sarcoma if patients are scheduled for nephrectomy.
Neoadjuvant Radiotherapy
Radiotherapy is widely used in the neoadjuvant setting for soft tissue sarcomas both in the extremity and retroperitoneum. The standard protocol involves patients receiving 50.4 Gy in 28 fractions over approximately 5 weeks. Side effects are mostly limited to the area being irradiated, with edema and inflammation of those local tissues. General effects such as fatigue are also well described. Local effects causing nausea and loss of appetite become specifically relevant in neoadjuvant irradiation of retroperitoneal tumors. These patients can rapidly become deconditioned during radiation therapy and require specific interventions and nutritional support to minimize these effects prior to surgery.
Targeted Therapies
The utility of molecular targeted therapies in sarcoma is minimal. Few tumors carry mutations that have available therapies. The exception to this are gastrointestinal stromal tumors (GISTs), the vast majority of which harbor mutations that respond to tyrosine kinase inhibitors (TKIs). TKIs can be used in the neoadjuvant, adjuvant, and advanced setting, and improve resectability, progression-free survival, and overall survival. Side effects include fatigue, gastrointestinal disturbances, skin changes, hypertension, and rarely cardiotoxicity.
Preoperative Care
Altering surgical stressors preoperatively can have an impact on postoperative morbidity and recovery. Obesity, poor glycemic control, smoking, and poor nutritional status increase the risk of postoperative complications. Interventions to improve these stressors and manage comorbidities prior to surgery, such as those parts of an Enhanced Recovery After Surgery (ERAS) program, or in isolation, should be considered in the sarcoma patient.
Prehabilitation
Prehabilitation has been likened to preparation for a marathon—working through all aspects around surgery to try and make the patient as “fit” as possible. Input from exercise physiologists, physicians, dieticians, and psychologists, and social support are all important. Interventions range from a single 30-min education session to structured exercise, and nutritional, medical, and psychologic support plans over multiple weeks. These interventions have been shown in small trials to halve the risk of postoperative complications. However, the benefits of prehabilitation should always be balanced by the possibility that the patient’s cancer could progress to being irresectable in the time to surgery and worsen the overall prognosis. Clear communication between team members is vital for good decision-making.
Intraoperative blood transfusion adversely affects overall cancer prognosis and independently increases postoperative morbidity. Although intraoperative strategies can be employed, every effort should be made to minimize the need for intraoperative blood transfusion by treating preoperative anemia, which is common in cancer patients. This can be in the form of intravenous iron infusion if time allows, or preoperative autologous blood transfusion. Preoperative allogenic blood transfusion can also be considered in extensive surgery if there is a poor response to iron infusion and a high likelihood of needing blood intraoperatively. Management of preoperative anemia may also improve the patient’s ability to exercise and therefore increase the benefit of prehabilitation.
Intraoperative Considerations
The main determinant of prognosis in surgically resectable sarcomas is that of a negative margin at resection, and this dictates the surgical strategy.
Bone
Over time, neoadjuvant therapies, imaging, and improved medical technology in the form of bone implants, prostheses and computer-assisted orthopedic surgery (CAOS) have allowed for more limb salvage surgeries rather than amputation. However, these remain extensive and challenging surgeries. Currently, approximately 85% of bony sarcoma surgery is limb salvage surgery. These procedures involve prolonged operations, requiring soft tissue and bone resection, replacement with prosthetic or grafted bone, and may need vascularized soft tissue reconstruction to cover the defect. Occasionally vascular resections are also involved. Blood loss can be significant. Postoperative intensive care support is often required.
Extremity Soft Tissue
Although these tumors can be simpler resections than primary bone tumors, they can also result in prolonged operative times due to the need for soft tissue reconstruction to fill defects. As with bone tumor surgery, the aim of surgery is to clear the tumor with a margin of normal surrounding tissue. The amount of normal tissue required depends on the type of tissue margin and the tumor histology. Studies have demonstrated that certain tissue types, more resistant to invasion, form the “equivalent of centimeters” of skeletal muscle or fat when determining the resection margin, thus allowing for salvage of abutting vital structures.
Retroperitoneal
As previously mentioned, retroperitoneal tumors tend to present late when relatively advanced due to the nature of such tumors to remain asymptomatic for prolonged periods. This means that they tend to be large tumors closely related to multiple organs at surgery. Commonly resected organs include the colon and kidney. Recent data from high-volume centers suggest that resection of adjacent organs where imaging does not necessarily show organ invasion is associated with improved disease control, as microscopic organ invasion is not readily seen on cross-sectional imaging.
Histologic Tailored Surgery
As previously mentioned, accurate histological diagnosis can change surgical planning based on the behavior of the sarcoma subtype. Tumors with higher risk of local recurrence require more aggressive local surgery with wider margins. An example of this is surgery for retroperitoneal liposarcoma, where high rates of recurrence make clear margins crucial. Improved prognosis for these tumors has been gained by more extensive multiorgan resection for these tumors, including ipsilateral kidney, colon, and mesocolon, to improve the chances of an R0 resection. In contrast, other retroperitoneal tumors such as leiomyosarcoma may require more extensive vascular resection, but surrounding structures can often be preserved.
Isolated Limb Infusion/Perfusion
Although limb salvage surgery is the standard of care in extremity sarcoma, there remains a group of patients without distant metastases whose sarcoma is not initially amenable to limb salvage. These patients could be considered for attempted limb salvage using isolated limb infusion/perfusion (ILI/P). ILI/P allows for high-dose locoregional therapy to the primary while allowing the patient to retain the affected limb and limiting the potential for systemic toxicity. This can reduce the disease sufficiently for it to become locally resectable and does not appear to be associated with worse overall outcomes (in a disease with a high propensity to metastasize). Infusion requires chemotherapy (typically melphalan based) to be circulated via radiologically placed catheters in a tourniqueted limb. Perfusion requires open surgical insertion of catheters, and the hyperthermic chemotherapy with added tumor necrosis factor-alpha (TNF-α) is circulated via an oxygenated extracorporeal perfusion circuit. Early complications include limb edema, skin loss, and rarely compartment syndrome and myoglobin-induced kidney injury.
Other intraoperative considerations are as follows.
Intraoperative Blood Loss
Intraoperative blood loss is a significant risk for patients undergoing sarcoma surgery. Hemostatic devices are commonly used to limit blood loss, but tumors are extensive and can be highly vascular. Certain anatomic locations such as pelvic dissection also predispose the patient to hemorrhage, and preoperative planning, including massive transfusion protocols, should be agreed upon in advance. Use of a cell salvage device to reduce the need for allogeneic blood can be considered but remains controversial in the setting of cancer surgery. There is concern that there may be viable tumor cells in the salvaged blood that could put the patient at higher risk of metastasis. Leucodepletion filters can be used to reduce the number of cells in the salvaged blood. However, this significantly increases the time it takes for salvaged blood to become available, which can limit its usefulness. It is advised that if cell salvage is considered, the patient specifically consents to the risks and benefits.
Bypass
Veno-venous, veno-arterial, and full cardiopulmonary bypass are rarely used in sarcoma surgery, but are options if facilities are available. Full bypass is usually reserved for cardiac sarcoma resection. Veno-venous or veno-arterial perfusion can be considered for retroperitoneal sarcoma resections that will require prolonged vascular clamp time, in order to maintain distal organ perfusion, minimize reperfusion injury, and simplify fluid balance during prolonged surgery. All the complications associated with major surgery on bypass, such as acute kidney injury, electrolyte abnormalities, platelet dysfunction, systemic inflammatory response, hyper- and hypothermia, cerebral injury, and immmunosuppression, can occur in these patients. There are no current international guidelines for perioperative antibiotics specific to sarcoma surgery. Antibiotics are widely used but choice of antibiotics and regimens differ.
Postoperative Care
The need for intensive care postoperatively is dictated by the length of surgery, type of procedure, and the underlying condition of the patient. With the increase in incidence of soft tissue sarcomas in elderly patients, these are often older patients who can be deconditioned due to neoadjuvant therapy, or simply due to their cancer. Extensive resections and prolonged operations often need intensive care support postoperatively and prolonged hospital stays.
Special Considerations
Enhanced Recovery Programs
There are no direct guidelines from the ERAS society regarding sarcoma surgery. However, gastrointestinal guidelines are easily extrapolated to retroperitoneal sarcoma surgery patients. Most ERAS principles can be applied to extremity surgery too. Programs such as those, including judicious use of intravenous fluid, early mobilization, minimal drainage, and early or no urinary catheter use among other things, have been used in Soft Tissue Sarcoma surgery centers with good results. ,
Extremity Surgery
The operated extremity is often placed in a fixed brace or dressing to limit movement that could damage the reconstruction. Early mobilization and rehabilitation by allied health staff using specific methods is needed, taking into account the surgery and specific reconstruction. ,
Thromboprophylaxis
Recently published international guidelines for venous thromboprophylaxis agree that sarcoma surgery places patients at high risk for venous thromboembolism, although guidelines specific to sarcoma are lacking. The use of postoperative thromboprophylaxis is wide but not standardized. Local protocols for dosing regimens and drug choice should be applied. Extended thromboprophylaxis for 4 weeks or longer is advised for intraabdominal and pelvic surgery.
Pain Control
Postoperative patients require multimodal analgesia beginning at the operative period. Combination analgesia makes use of opioids, nonsteroidal antiinflammatories, regional anesthesia such as blocks and epidurals, and other agents to treat pain in a proactive fashion from the start of the surgical stimulus. Good patient communication and multidisciplinary input from pain and allied health staff also play a role in postoperative pain management.
Conclusion
Sarcomas represent a heterogeneous group of diseases in anatomically varied locations, can be clinically complex to manage, and show a range of biological behaviors. Surgery has been the backbone of management, but a tendency to both local recurrence and distant metastasis in a number of subtypes suggests a poor prognosis. However, multidisciplinary management with a focus on careful and appropriate histologic diagnosis and histology-tailored treatment is associated with the best outcomes for patients.
Perioperative Care: Melanoma
Introduction
Melanoma is a mesenchymal malignancy of melanocytes, occurring wherever melanocytes are found. This leads to three principal subtypes, namely cutaneous, ocular, and mucosal, each with their own distinct tumor biology and behavior. Cutaneous melanoma makes up the large majority of cases. Most patients present with early-stage local disease. However, the management of patients with metastatic melanoma has seen the most dramatic change over the last decade. The introduction of effective systemic therapies both with checkpoint blockade immunotherapy (CBI) and molecular targeted therapies has induced profound responses in patients with metastatic disease. Similar responses are seen using these agents in the adjuvant and neoadjuvant setting. This has similarly resulted in changes in anesthetic and surgical management of later-stage melanoma.
Cutaneous melanoma is a rare skin cancer, with a variable global incidence (worldwide average, 22 per 100,000), and the peak being in Australia and New Zealand at 49 per 100,000 people. There are marked differences in melanoma incidence across different races (and therefore skin types), with the incidence of melanoma in white males in the United States being 27 times higher than in black males. There are also geographic differences, with higher incidences noted at lower latitudes. The geographic effects span skin types. Cutaneous melanoma occurs across all ages, with the incidence increasing with age. It remains rare but not unheard of in the pediatric and adolescent population.
UV exposure is the most important risk factor for melanoma development. Intermittent exposure in early life appears to be the highest risk, with more than five early sunburns increasing the lifetime risk of melanoma twofold. Use of indoor tanning beds also increases the risk of developing melanoma proportional to the amount of use, further reinforcing the association with UV exposure.
Other risk factors include phenotypic traits, such as skin type, and type, and number of naevi. Familial melanoma clusters are thought to be a combination of genetic predisposition, common heavy sun exposure, and phenotypic risk factors. Numerous other risk factors have shown small increases in risk, including immunosuppression, nonmelanomatous skin cancers, and others.
Mucosal melanomas are very rare, occurring most commonly in the upper aerodigestive tract, the vulvovaginal area, and the anorectal tract. They generally have a poor prognosis, present later, and are at high risk of distant metastases. Ocular melanoma develops in the choroid, ciliary body, iris (uvea), or conjunctiva. These often late-presenting tumors can be managed initially with eye conserving local therapies. Patients are at high risk of metastatic disease despite adequate local control, predominantly in the liver. Given the rarity of mucosal and ocular melanoma, the remainder of this review will discuss patients with cutaneous melanoma.
General Principles
Preoperative Workup
After presenting to their general practitioner or dermatologist with a skin lesion, subsequently biopsied, patients will often present to their surgeon with a histologically confirmed diagnosis. The extent of preoperative workup is determined by the tumor Breslow thickness (maximal depth of skin invasion). Axial imaging can be used to rule out metastatic disease at presentation. Evidence of benefit is limited in asymptomatic patients. FDG-PET can be considered for staging in thick melanomas. Clinical evidence of nodal disease (either palpable or found on radiology) requires ruling out of further metastatic disease prior to proceeding to surgery.
Surgical Principles for the Management of Cutaneous Melanoma
Wide excision of the primary site is aimed at preventing local recurrence of the melanoma. The width of the margin around the primary lesion or biopsy site is dictated by the thickness of the melanoma, varying between 1 and 2 cm of normal skin around the lesion. Closure may require local flap reconstruction or skin graft, depending on the location.
Sentinel lymph node biopsy is used to provide lymph node staging and is regarded as one of the most important prognostic stratification tools. Accurate localization of the first draining lymph node in the relevant nodal basins requires the use of intradermal injection of localizing agents. Use of dual tracers combining radiolabeled nanocolloid with patent blue dye decreases the risk of removing a false negative sentinel node.
Radiolabeled nanocolloid is injected, and single photon emission computed tomography (SPECT) imaging with or without the use of low-dose Computerised Tomography (widely used abbreviation) localizes the draining nodal basins and number of sentinel nodes. A small incision is made, and the sentinel node removed. The node is identified by using the gamma probe intraoperatively to identify the radioactive lymph node. Intradermal injection of blue dye at the primary site on the theater table provides visual confirmation by coloring the sentinel node.
Wide excision alone can be performed under local anesthetic. Sentinel lymph node biopsy usually necessitates general anesthetic.
Intraoperative Considerations
Melanoma occurs across all ages, but is more common in the elderly, and this should be borne in mind when considering anesthesia. Most surgery for patients with primary melanoma is a simple day surgery procedure of wide excision with or without sentinel lymph node biopsy. Where sentinel node biopsy is not required, surgery can often be done under local anesthetic alone. Wound closure may require local procedures such as advancement, rotational, or island-type flaps but seldom more than this. Skin grafts may also be required.
Methylene or patent blue is widely used as the second tracer in dual modality sentinel node biopsy, and injected intradermally as the case begins. This carries a 0.9% risk of allergic reactions. Awareness and close monitoring of all cases is essential.
Isolated Limb Infusion/Perfusion
This procedure is used for patients with regionally advanced melanoma with multiple unresectable dermal or subcutaneous metastases. The limb is isolated with an arterial tourniquet and high-dose administration of cytotoxic drugs can provide responses in up to 75% of patients. Limb infusion is simpler than limb perfusion, requiring image-guided cannulation of the relevant vein and artery, tourniquet isolation of the limb and circulation, and then flushing of the cytotoxic agent. Risks include reperfusion injury, rhabdomyolysis, acute kidney injury, vascular injury, and delayed compartment syndrome and skin complications.
Perfusion requires open vascular cannulation and use of bypass equipment to actively circulate oxygenated blood and cytotoxic drugs.
Postoperative care seldom requires intensive care or prolonged hospital stays, and care should be focused on rapid mobilization and return to normal life.
Surgery for “Immune Escape” Lesions
Surgical resection of oligometasatic lesions progressing on CBI is evolving. These lesions may be primary progressors (where all tumor deposits respond to the therapy except for a single lesion that continues to grow) or secondary progressors (where an initial complete or near-complete response is followed by isolated progression). Surgical resection of the isolated progressing lesion is associated with a good outcome. This can obtain durable disease control. Importantly, it is likely that patients with this type of progression have other sites of disease that remain in equilibrium under ongoing immune control. Therefore there is a strong theoretical basis for avoiding any immunosuppression in these patients.
Systemic Therapy
Immunotherapy
Although the concept of immunomodulation to treat melanoma has been used for decades, the identification of immune checkpoints such as CTLA4 and PD-1 and the effective inhibition of these have significantly improved the effectiveness of this approach. CBI works by binding and inhibiting specific receptors that downregulate the host immune response to the tumor, releasing the brakes on the immune response. These allow the host’s own immune system to identify and eradicate the tumors. Multiple receptors can be targeted by antibody infusions, including PD-1, PD-L1, and CTLA4 amongst others. This is a rapidly expanding field of cancer therapy used across multiple tumor types and the applications are constantly growing. Responses to single agent and combination therapy are 40% and 55%, respectively, with a 15%–20% complete response rate. Up to 80% will have a heterogeneous response to treatment, with lesions responding differently requiring other modalities for treatment.
Complications of immunotherapy, although less commonly severe than those caused by traditional chemotherapy, can be significant. Known as immune-related adverse events (IrAEs), use of checkpoint inhibitors can result in immune infiltrates in almost all organ systems, resulting in autoimmune disorders. These include colitis, pneumonitis, myocarditis, hypophysitis, nephritis, thyroiditis, hepatitis, and skin disorders, amongst others. Although fatal IrAEs are rare, the highest risk of death is from immune-related colitis. The incidence of more severe IrAEs (grades III–V) varies from 10% to 31% depending on the agent used, and combination immunotherapy, although more effective, carries the highest risk of severe adverse events of all. Adverse events are managed by cessation of immunotherapy and initiation of systemic corticosteroids, oral or intravenous, depending on the severity of the IrAE. Steroid requirements can be prolonged following an IrAE and should be borne in mind. Hypophysitis can also result in lifelong steroid dependence and inability to mount an appropriate stress response.
Immunotherapy can also cause flares of previous autoimmune diseases and requires cessation of immunosuppressive treatments. Decision-making and planning can be complicated, and multidisciplinary discussion is mandatory for example, for transplant recipients.
There is currently no evidence that immunotherapy should be paused for surgery, and no clear data on timing of surgery related to dosing in well patients.
Targeted Therapy
Approximately 40% of melanomas carry the driver BRAF genetic mutation that can be targeted therapeutically. Patients whose tumors harbor an actionable BRAF mutation can be treated with agents targeting BRAF and MEK. Combined blockade results in both higher response rates and lower rates of certain toxicities. In most patients, the tumor will develop resistance mechanisms to therapy. Combination targeted and immunotherapy approaches are under investigation but toxicities are high. Targeted therapy can be used both in the neoadjuvant and adjuvant setting.
Complications commonly include pyrexia, chills, fatigue, diarrhea, and photosensitivity, depending on the agents of choice. Rarer complications more relevant to the surgical population include new-onset hypertension, left ventricular dysfunction, and alteration in liver enzymes. These should be borne in mind during preoperative review.
Neoadjuvant Therapy
Neoadjuvant therapy with either immunotherapy or targeted therapy in appropriately selected stage 3 and resectable stage 4 patients is in its infancy. Early trials show promising relapse-free survival in patients who have received either regimen and had major or complete pathologic responses in their resected specimens. However, this is not a risk-free approach, as the possibility that there could be disease progression in the interval between therapy and surgery remains. There is also a risk of toxicity from the neoadjuvant therapy that could delay surgery. Although early reports do not suggest an increased risk of surgical complications, anecdotal evidence indicates that surgery may be more challenging after neoadjuvant therapy. A number of prospective trials are currently underway.
Modern randomized controlled trials (RCTs) have changed the face of melanoma surgery. Surgery will continue to shift as access and efficacy of immunotherapy and targeted therapies improve. Fewer lymphadenectomies are performed than ever before, simplifying the surgical burden. The majority of melanoma surgery is limited to primary excision with or without complex wound closure and sentinel node staging. This allows for more procedures to be performed under local or regional anesthesia, according to preference and patient factors.
Beta Blockade
A number of observational studies across multiple cancer types show promise for the use of beta blockers to limit cancer progression based on the theory that blocking beta-adrenergic receptors can inhibit pathways that cause progression. Long-term follow-up of one of these cohorts in melanoma shows improved overall and melanoma-specific survival.
However, these results remain controversial with many of the studies being subject to methodological flaws. A large meta-analysis of specific melanoma patients showed an improvement in overall rather than cancer-specific survival, suggesting the benefits are not related to prevention of melanoma progression. Randomized evidence is awaited.
Conclusion
Melanoma management is a rapidly evolving field, undergoing rapid changes as systemic management becomes the mainstay for later-stage melanoma. Early-stage melanoma is still managed by simple surgical and staging procedures. The role of extensive surgery for patients with melanoma is changing as systemic therapies are used in earlier stages of disease.
References
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