Neoplastic disease is one of the leading causes of death worldwide with an incidence of 14 million in 2012, resulting in 8.2 million deaths [16]. Oncological management is complex and multimodal, often requiring combination of chemotherapy, radiation, and surgical intervention for definitive or palliative treatment. Aside from their role in solid tumor diagnosis and management, surgeons manage acute surgical interventions either separate from or influenced by the primary disease. Thus, basic knowledge of chemotherapy and its effect on immunosuppression is of utmost importance.

Chemotherapy ideally reduces disease burden by decreasing tumor size, halting disease progression, and abolishing micrometastases. In general, antineoplastic drugs act at the cellular level to reduce rapidly proliferating cells [17]. As a result, these drugs damage healthy cells with similar characteristics residing in the bone marrow, gastrointestinal tract (GI) and skin tissue. Immunosuppression and myelosuppression are of particular interest in perioperative management. This section will focus on common perioperative presentations and surgical implications of side effects encountered during antineoplastic therapy.

Chemotherapy agents are divided into alkylating agents, antitumor antibiotics, antimetabolites, plant alkaloids, hormonal therapy, and targeted tissue therapy [17]. Many of these agents function to inhibit the cell cycle in a phase-specific (antimetabolite, vinca alkaloid, and bleomycin) or non-specific manner (alkylating agents and antibiotics) [17]. A summary of side effects is found in Table 22.3.

Chemotherapy regimens are often used as combination therapies to target different pathways in the neoplastic process. Each medication’s metabolism, half-life, and excretion pathway influence its toxicity profile. Further, toxicities may contribute to or exacerbate coexistent comorbidities and polypharmacy exacerbates these issues [18]. For instance, cardiotoxicity and cardiac injury are common adverse effects of antimetabolites such as doxorubicin. Thus, preoperative cardiac evaluation must be enforced. Pulmonary toxicity is common with bleomycin, methotrexate, and mitomycin C therapy resulting in early plain radiological findings of fine, reticular bibasilar infiltrates. Clinically, these findings may affect anesthesia delivery and hemodynamic response. Methotrexate and azathioprine have been linked to hepatic fibrosis and intrahepatic cholestasis, respectively [18]. Renal toxicity is common among platinum compounds, methotrexate, and streptozocin but can be avoided with adequate hydration and avoidance of simultaneous use of renal toxic compounds such as aminoglycoside antibiotics. Nitrogen mustards such as cyclophosphamide and ifosfamide often cause hemorrhagic cystitis. This is a self-limiting effect and cease after discontinuation of therapy. Treatment with mesna for hemorrhagic cystitis is useful, but definite treatment may require cystoscopy-assisted hemostasis through electrocautery or sclerosis with formalin [18]. Early manifestations of neurotoxicity include neuropathy and hyporeflexia. However, neurotoxicity may progress to SIADH, tinnitus, hearing loss, autonomic instability, cranial nerve palsies, and emesis related to alkaloids, antimetabolites, or platinum agents. Emesis is a common ailment and should be readily anticipated and treated prior to chemotherapy induction.

Myelosuppression is dose limiting in many antineoplastic regimens, yielding reduced production of blood cell precursors approximately 2 weeks after induction. This cytopenia is commonly transient, lasting several days, but marked by neutropenia and absolute neutrophil count (ANC) <1000 cell/mm³ [19]. Neutropenic patients lack the classic signs of infection (erythema and elevated cell counts) and most frequently present with fever as the sole complaint in 25–40 % of patients. Hypotension, weakness, and confusion may also occur. The source of the fever is rarely found, warranting implementation of antimicrobial therapy per Infectious Diseases Society of America (IDSA) guidelines for neutropenic patients [20]. These guidelines recommend expanded broad-spectrum coverage for gram-negative and anaerobic organisms with piperacillin–tazobactam or a carbapenem [20]. Combination therapy with antipseudomonal cephalosporins plus metronidazole is also appropriate. Therapy should be continued until resolution of symptoms and objective signs of improved neutrophil count (ANC >500 cell/mm³) [20]. Antifungal coverage should be started with amphotericin B in the setting of continued fever, neutropenia, and clinical deterioration or lack of improvement after 5 days of adequate antimicrobial coverage. Addition of colony-stimulating factor (CSF) to boost immune response can be considered in septic patients or if ANC falls below 100 cell/mm³ [20].

Achieving the ideal chemotherapeutic regimen includes a balance between maximizing tumor suppression and local control, and minimizing toxicity and immunosuppression. Surgeons must be able to recognize and properly evaluate antineoplastic drug toxicities in preoperative planning to reduce surgical complications. Appropriate treatment for neutropenia should focus on antimicrobial therapy and boosting the immune system prior to surgical intervention.

The use of targeted biologic therapy has emerged as a suitable approach for patients with rheumatic and autoimmune diseases. The mechanism of action of these agents includes reduction of chronic inflammatory changes by targeting cytokines, inflammatory cells, and costimulation molecules [21]. Considering risk and benefits of primary disease flare with serious infections from surgical complications is an important distinction.

Cytokines such as tumor necrosis factor (TNF-α), Interleukin-1 (IL-1), and Interleukin-6 (IL-6) have major roles in endothelial cell activation, promoting inflammation, coagulation, wound healing, and hepatic synthesis of acute phase reactants [21]. IL-6 is also known for B-cell activation and antibody proliferation. Additionally, cluster of identification (CD) molecules are cell surface molecules involved in activation of B and T lymphocytes particularly CD 20, 22, and 28 [22]. Drugs that target these pathways are of particular importance for the management of chronic inflammatory and autoimmune conditions. Table 22.4 includes a list of currently FDA-approved agents and indications for use.

The initiation of biologic treatment requires screening for previous or current tuberculosis infection, serological evidence of viral hepatitis, and previous or current malignancy. This is important as therapy with biologics can induce reactivation of latent infections [23]. Risks of myelosuppression and decreased wound healing are also prominent [24]. This infection risk is heightened by the inherent risk of autoimmune diseases. For instance, RA patient have been found to have a 13-fold increase in infection risk when compared to healthy controls in the absence of immunosuppressive regimen [25]. Interestingly, there is a lack of recommendations regarding continued use of biologics in the perioperative period but most supports cessation of therapy should be practiced when possible.

Anti-TNF-α agents have emerged as effective therapies for inflammatory bowel disease. Rituximab, originally used in the treatment of lymphoma, is a monoclonal antibody against CD 20 cells, which represses a subset of B cells via apoptosis [24]. It is approved for use in autoimmune disorders and lymphocytic malignancies but is also used off label for auto-autoimmune disorders (idiopathic thrombocytopenic purpura), desensitization of ABO blood groups in transplant incompatible patients, and dermatologic disorders [24]. IL-1 inhibitors, such as Anakinra, have few clinical indications and a short half requiring daily injections and common development of skin tissue infections at site of injection. Surgical implications of biologic are discussed separately in this chapter.

The total number of transplants performed in the USA in 2011 reached over 29,000 [26]. Many transplant recipients are experiencing longer survival in part due to better understanding of pathophysiology involved in rejection, improvements in immunosuppressive therapy, and more efficient immunosuppressive agents combination strategies. Post-transplant immunosuppression is typically achieved with glucocorticoids, calcineurin inhibitors, antiproliferative, and/or antimetabolic drugs [18]. Surgeons must have an understanding of these immunosuppressive therapies for appropriate management of acute and elective interventions (Table 22.5).

Glucocorticoids are the oldest medications used in transplant immunosuppression. Immunosuppression is achieved by reducing T-cell proliferation, inflammatory cytokines, vasodilatory molecules, tissue permeability, and preventing monocyte migration [27]. They exert their role by binding to intracellular receptors and modulating cellular transcription [27]. Initial administration results in neutrophilic leukocytosis, eosinophilia, and lymphocytopenia. Interestingly, while there is a reduction in total number of B cells, immunoglobulin production is preserved [28]. Additionally, T-cell apoptosis results in impaired cell-mediated immunity [27]. The side effect profile of corticosteroid depends on amount, steroid potency, mineralocorticoid profile, and the length of treatment. Major side effects include hypertension, cardiovascular disease, hypokalemia, adrenal insufficiency, diabetes, visceral perforation, and higher risk of infection. Surgical complications and perioperative management in the setting of steroid use deserve further consideration and will be addressed later in this chapter.

Calcineurin inhibitors (CNI) are the most commonly used agents post-transplantation and include tacrolimus and cyclosporine (CsA). These agents substantially decreased organ rejection and revolutionized transplant immunosuppression when first introduced. Their mechanism of action involves blockage of NFAT (nuclear factor of activated T cells) transcription reducing cytokine release from T cells [29]. Dosage requires close monitoring due to narrow therapeutic range contingent on type of organ transplant. Oral administration requires GI absorption, P450 hepatic metabolism and bile excretion [29]. Thus, any metabolic (P450 inducer/inhibitor), physiological (alteration of GI flora, diarrhea, inflammation), or mechanical process can affect CNI metabolism. CNIs have nephrotoxic, neurotoxic, metabolic, and endocrine side effects [29]. The nephrotoxic effects are particularly important after renal transplant often requiring dosing reduction or selection of different agents. Avoiding concomitant use of nephrotoxic drugs such aminoglycosides is strongly encouraged. Neurotoxicity presents as seizure, confusion, coma, tremors, or headache [30]. Multiple electrolyte and metabolic derangements also occur including hyperglycemia, hypomagnesemia, and hypercholesterolemia [31]. Tacrolimus-induced hyperglycemia occurs by establishing insulin resistance that is further exacerbated by surgical stress. Postoperative treatment with a sliding insulin regimen may be required in a patient with otherwise adequate intrinsic glucose control [31]. Higher incidence of ischemic events (CVA and MI) complicates preoperative planning and places these patients at higher risk [31].

Antiproliferative and antimetabolic drugs include azathioprine, mycophenolic acid, mycophenolate mofetil (MMF), sirolimus, and everolimus. Azathioprine, often used in chemotherapy, interferes with DNA synthesis by incorporating false nucleotides (6-thio-GTP) into replicating strand of rapidly proliferative cells such as B and T lymphocytes [32]. Main adverse effects of azathioprine include hepatotoxity, pancreatitis, and dose-limiting myelosuppression [32]. MMF and mycophenolic acid inhibit purine synthesis and have similar preference for fast replicating cells, thus sharing side effects of azathioprine. Sirolimus (Rapamycin) and everolimus, similar to tacrolimus, reduce lymphocytic activation by inhibition of mTOR (mechanistic Target of Rapamycin) and IL-2 signaling [33]. Sirolimus has a preferred renal profile over CNI and is often used as maintenance in renal transplant. However, these agents induce severe leukopenia and thrombocytopenia. Sirolimus also decreases wound healing resulting in dehiscence and incisional hernias particularly in obese patients with BMI >32 kg/m² [33]. In this group, it is beneficial to switch to CNI therapy for elective surgeries for two to four months prior and restarting 6-week postoperatively to improve wound healing.

Mucosal injury and ulceration are common ailments among transplant immunosuppressive therapy. Diarrhea and GI side effects are more common with tacrolimus, CsA, and MMF in a dose-dependent fashion [34]. A proposed mechanism for MMF-associated diarrhea includes inhibition of cryptcell division and loss of duodenum villous structure [34]. Ulceration of the GI tract is multifactorial, but has been associated with utilization of NSAIDs, surgery stress, and impaired cytoprotection of mucosal defenses from decreased cell turnover [34]. GI bleeding, when it occurs, is often secondary to undiscovered ulceration. Lung transplant patients may acquire giant gastric ulcers, defined as ulcers with diameter >3 cm, resulting in high mortality secondary to bleeding [34]. Identifying patients with risk factors for GI ulcers is difficult and low threshold for routine endoscopy with biopsy in symptomatic patients is endorsed. Standard practice should include ulcer prophylaxis with PPI or H2 blockers. Perforations can occur throughout the GI tract secondary to steroids, diverticular disease, and concomitant NSAIDs use. Transplant recipients are also at increased risk for biliary tract disease from calculi influenced by cell turnover, resulting in emergent cholecystectomies with high mortality rates. In renal transplant recipients, cyclosporine has resulted in reduced bile flow and increased incidence of cholelithiasis [34]. Therefore, elective surgery for eradication of biliary pathology and ultrasound screening should be practiced during the post-transplantation period to improve outcomes. Acute pancreatitis, although uncommon, carries increased mortality rates of 64 % in liver transplants and 100 % in renal transplant patients [33]. Risk factors for acute pancreatitis include immunosuppressive agents, CMV, HBV, hypercalcemia, alcohol, cholelithiasis, and malignancy [34]. Follow-up with CT at regular intervals to identify unusual inflammation, pseudocyst formation, edema, or necrosis is beneficial. Treatment for acute pancreatitis must focus on aggressive intravenous fluid resuscitation, fasting, identification, and cessation of inciting agent followed by surgery when clinically indicated [33].

Infectious complications are of particular importance in transplant patients due to the nature of chronic immunosuppression. As previously addressed, atypical presentation of infection is common among this group of patients and the clinician must be alert and cautious during preoperative planning. Lung transplant recipients experience invasive early and late fungal infections with coccidiomycosis and aspergillus, respectively [35]. Prophylactic treatment with fluconazole is recommended for the former [36]. Cutaneous and anogenital lesions should raise concern for HPV infections and marked immunosuppression requiring biopsy and surveillance [37]. Finally, CMV infection is the most common infection among post-transplant recipients and is associated with allograft rejection, EBV post-transplantation proliferative disorder (PTLD), and high rate of mortality in the first 6 months [38].

Transplant patients represent a complex mixture of pathologies requiring multidisciplinary collaboration between physicians (transplant, infectious diseases, PCP, and surgeons) for appropriate management and risk reduction. When appropriate, termination or substitution of immunosuppressive regimen improves surgical outcomes.