Complications Across the Cancer Care: A Comprehensive Review of Surgical, Radiological, and Systemic Toxicities

The current state of globally viewed cancer (or oncology) demonstrates that while there are falling cancer death rates largely due to the development of new and/or earlier detection methods, there will be more than 18.6 million people in the United States alone who have a past history of cancer and survive; this number may grow to over 22 million by 2035.(1) For cancer survivors this requires understanding not only how the different types of cancer treatment (i.e., surgery, chemotherapy, and radiation therapy) can have negative long-term effects on their health but also many of the newly developed forms of cancer treatment (i.e., immunotherapy and/or CAR T therapy) can have detrimental and long-lasting health consequences for them as well. Collectively these 18 million cancer survivors often live with multiple and complicated types of physical health and mental health problems that can last many years beyond completion of their cancer treatment. (2, 3)

Epidemiological Context and the Growing Burden of Survivorship

Since many of the treatments used today are multimodal, the oncologist has to deal with the complications that arise from using various therapy agents through their entire course of therapy. (4) As an example, adding on immunotherapy to a patient’s existing chemotherapy regimens will improve their overall survival; however, it also creates an unknown range of irAEs (immune-related adverse events) and complicates the care for the patient as more than 70% of patients experience this complication with no previous experience with these complications occurring in practice. (5)

Table 1. Global Cancer Burden and Survivorship Projections (2025–2035)

The statistics collected regarding cancers reflect continuing inequalities, such as Native Americans having the highest death rates from cancers affecting the kidneys, stomach, and cervix, due to the systemic barriers to receiving equitable treatment and care; in addition to this, the effects of the COVID-19 pandemic will have a ripple effect throughout the cancer industry and delayed diagnoses in 2020 will potentially create an increased burden of advanced-stage disease by mid-2025.(6, 7) Pathophysiology of Surgical Complications Associated With Cancer Surgery; Cancer surgery is a key curative treatment, however is also associated with complications that can affect long-term oncological success. One of the most prevalent complications associated with odorless cancer surgery is adhesion formation, which occurs in approximately 95% of individuals; further, adhesions are the most frequent cause of SBO. (8)      

Colorectal and Abdominal Surgical Sequelae

Frequently, people will have an ileus after they undergo colorectal (colon) surgery (after the bowel is opened, etc) There is evidence that 10% of patients who get their colon surgically fixed will develop an ileus post-operatively and that the distance between the two surgeries (whether laparoscopic or open) is irrelevant.(9, 10) Patients with an ileus will initially be treated by decompressive bowel management (either through liquid diet or suctioning), but most of them will eventually require laparoscopic treatment (adhesiolysis is currently the most common laparoscopic procedure performed) to remove adhesions that form when the intestine lays down any number of tissues in a person's abdomen due to healing, and this appears to facilitate a faster recovery. There are, however, no standardized guidelines for when this procedure should be performed and there are possible complications including potential increased risk of recurrent ileus following laparoscopic adhesiolysis. Additionally, there is evidence to support the occurrence of an ileus after malignant neoplasm surgery, which is also referred to as a thromboembolic event (thrombotic event) and surgical patients are primarily at risk for developing VTEs within 30 days of their surgery. (11)

Breast Cancer Surgery and the Prometastatic Environment

Special Considerations During Breast Cancer Surgery Research has recently focused on the relationship between post-operative complications (POCs) and breast cancer reoccurring. (12) A "Major Surgical Complication" (a complication that requires readmission or reoperation within a designated time frame) occurs in 5.9% of women who have undergone breast surgery. Surgical trauma associated with these complications has been shown to stimulate the growth of occult micro-metastases through the activation of pro-metastatic signals in a systemic manner.9 During postoperative wound healing, the release of inflammatory cytokines (e.g., interleukin-6, and tumor necrosis factor) is believed, by some, to inadvertently support the growth of occult micro-metastatic disease. (13, 14)

Table 2. Surgical Complication Rates by Procedure Type

As noted previously, while small SSIs may not significantly affect the chance of dying from breast cancer, major systemic infections increase the likelihood of systemic recurrence and overall mortality." This shows that de-escalation strategies are crucial in breast surgery where, when feasible oncologically, BCS is preferred to mastectomy in order to reduce POC occurrences. (15)

Thoracic and Urological Surgical Challenges

Lung cancer surgery has become less invasive, providing lower physiological demands on surgical patients since they often have multiple tobacco-associated medical problems (co-morbidities).12 Patients with a forced expiratory volume (FEV1%) of less than 35%, based on the normal prediction, have a substantially greater risk of acute failure from respiratory failure following surgery.12 An additional example of this is men who have had a radical prostatectomy may experience stress urinary incontinence that adversely affects their quality of life. Nightly waterworks have been the preferred method of treatment since 1970. To treat mild-to-moderate incontinence, use of newer transobturator male devices that can be adjusted postoperatively provide a safe and effective alternative to the older urinary sphincters, provided no manipulation is needed for voiding (sitting to urinate). (16, 17)

Radiation Therapy- Acute versus Delayed Injury from Radiation Therapy

The mechanism of cell death caused by radiation therapy is primarily due to DNA damage and free radical generation caused by oxidative stress.14 An example of the impact of radiation on the body is the clinical manifestations of radiation-induced toxicity (RIT).

The effects of RIT (Acute and Late) are dependent on the time after the patient has been exposed to the radiation, the tissue/organ turnover rate, and the affected tissue/organ's rate of cellular division. (18)

Table 3. Radiation Toxicity Timeline and Clinical Manifestations

System-Specific Radiation Toxicities

Radiation can lead to early and late effects. The heart and lungs are most commonly affected by late effects of radiation exposure. Radiation associated to cardiotoxicity (RACT) can present as myocardial infarction, congestive heart failure (CHF) and/or valvular disease that occur or more years after treatment. Among pediatric survivors, 29% of these patients develop valvular disease with a significant number of patients having aortic regurgitation and/or aortic stenosis. The most common pulmonary toxicity occurs as radiation pneumonitis followed by increasing pulmonary fibrosis which results in dramatically reduced pulmonary function can have permanent consequences. (19, 20)

Table 4. Organ-Specific Radiation Complications and Management

Technological advancements for radiation therapy, including image-guided radiotherapy (IGRT) and adaptive radiotherapy, offer us the ability to make real-time adjustments in treatment based on changes to patients' anatomy.19 In addition, the use of particle therapy (protons or carbon ions) takes advantage of the "Bragg peak" phenomenon, allowing us to concentrate the majority of the dose at the tumor site while limiting the irradiated dose to adjacent normal tissues. (21)

Systemic Therapy - Diverging Profiles for Chemo, Targeted and Immunotherapy

The development of systemic therapy has added significant diversity to the landscape of toxicities resulting from anticancer treatments; however, the mechanisms of action and timing of these toxicities vary widely within these three classes of systemic therapy. While cytotoxic chemotherapy is a non-selective agent that targets all cycling cells, targeted therapy and immunotherapy are more selective and utilize identifiable molecular and immunological processes. (22, 23)

Cytotoxic Chemotherapy: The "Carpet Bombing" Approach

The biggest disadvantage of traditional chemotherapy is its inability to differentiate between rapidly dividing cancerous and rapidly dividing healthy cells. (21) This problem creates the same complications found in many different cancers with fatigue being the most common symptom of the chemotherapy associated with fatigue. Cancer patients will report fatigue as a debilitating and not just tiredness caused by anemia, oxidative stress and metabolic activity associated with tissue repair. The leading cause of chemotherapy related hospital admissions is due to hematological toxicity. (24)

Anemia occurs in 763.7 out of every 1000 person-years of use and febrile neutropenia occurs at 295.7 per 1000 person-years, and thrombocytopenia occurs at 212.8 per 1000 person-years. (25) The peak incidence of these complications typically occurs in the initial months of treatment and causes the need for closer monitoring and more frequent use of growth factor therapy.

Targeted Therapies: Molecular Precision and Off-Target Effects

Precision in the Molecular Realm with Off-Target Outcomes

Targeted therapy is directed toward a specific genetic change, such as EGFR, ALK, or VEGF, with the help of either small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies. (21) Though they may spare patients from the alopecia or severe neutropenia produced by traditional chemotherapy, they can produce their own unique side effects, many of which are chronic, and will impact the patient's daily life on an ongoing basis.

EGFR inhibitors (e.g., osimertinib and erlotinib) are particularly well-known for their skin side effects (i.e., acneiform rashes) as well as their gastro-intestinal side effects (i.e., diarrhea). VEGF inhibitors (e.g., bevacizumab) can inhibit angiogenesis, thereby creating elevated blood pressure, deleterious effects on the kidneys, as well as delayed wound healing and other side effects. For that reason, agents that inhibit VEGF are generally considered contraindicated in patients who have squamous cell lung carcinoma due to the potential for developing rare cascade-type complications such as intestinal perforation or serious pulmonary hemorrhage. (26, 27)

Table 6. Targeted Therapy Toxicity Profile

A major finding from meta-analyses completed in late 2024 found that, compared to first-generation EGFR Inhibitors (3.2 percent) third-generation’s association with cardiac adverse events (9.5 percent) was more than 3 times greater; arrhythmias (7.3 percent) and heart failure were also present making regular and baseline cardiopulmonary testing necessary in patients receiving osimertinib. (28)

Immunotherapy's function is dependent on its mechanisms targeting the CTLA-4, PD-1 and PD-L1 immune checkpoints.(6) By targeting these immune checkpoints with immune check inhibitors (ICIs), they are thought to disinhibit or lift the “brakes" (downregulate) on the immune system, which allows the immune system’s attack on their target cells.6 However, immunostimulating agents induce specific organ-level inflammation and autoimmunity that are not seen with the majority of chemotherapeutic agents and the timing of organ-Level-specific inflammation or autoimmunity.6 In contrast to the rapid onset of typical chemotherapeutic therapies, iirAEs have a delayed (days, weeks or months) onset following the initial infusion or administration of the agent, and in some cases can occur even after the agent has been stopped for an extended period of time.(29, 30)

Table 7. immunotherapy Related Adverse Event management

Compared to monotherapy, combination therapies (like using ipilimumab with nivolumab) show a substantial (nearly 40%) increase in the rate of severe, Grade 3–4 immune related adverse events (irAEs)6. The rate of multisystem irAEs (irAEs that involve more than one organ system) in patients receiving monotherapy is between 5 and 9% whereas for patients receiving combination blockades, it is up to 40%35. An example of a critical management tool that high-volume centres have developed is a multidisciplinary irAE board (e.g., IMMUCARE) that brings together oncologists and organ specialists (e.g., nephrologists, rheumatologists, etc.) to discuss difficult cases. (31)

Multidisciplinary irAE boards are particularly important when making decisions regarding the potential rechallenge of immune checkpoint inhibitors (ICIs) after severe toxicity since this decision will typically lead to a definitive contraindication to rechallenge in 26% of debated cases.(32)

Associated Complications of Hematologic Malignancy Treatments: Transplantation and CAR-T Therapy

Leukemia and lymphoma treatment involves managing the complications associated with the underlying diseases that warrant treatment, such as the occurrence of GVHD during BMT and cytokine release syndrome (CRS) after CAR T-cell therapy. (33)

Graft-versus-Host Disease (GVHD)

The most common complication from allogeneic transplants is GVHD, which develops when donor T-cells attack host tissues. (3) Since acute and chronic GVHD has a different clinical picture, the following briefly describes their respective presentations:

Acute GVHD typically arises before day 100 or so post-transplant and typically affects three main organ systems: skin (which presents as a rash), liver (elevated bilirubin levels), and GI tract (i.e., diarrhea). (41) Chronic GVHD can be found for up to 50% of transplant recipients and has a much broader clinical presentation, including dry eyes, ulcers, and wrist/ankle joint stiffness. (4) The primary cause of death in chronic GVHD is infection which is why it is vital to have adequate infection prophylaxes and to involve a mult-disciplinary team. (34)

CAR T-Cell Therapy and Secondary Malignancies

While some experts believe that the increased rate of second cancers (SPM) developing after CAR T-cell therapy is due to the longevity these patients obtain after receiving such treatment (which provides a survival benefit) and that many of the same recipients have already been exposed to an increased risk of cancer as a result of prior chemotherapy/radiation; based on studies conducted in 2024-2025, the incidence rate of SPM among CAR T-cell patients (5-8.5%) appears similar to the incidence rates of SPM among patients treated with other modalities. As per the above-mentioned studies (2024-2025), the most common types of SPM seen following CAR-T therapy are hematologic malignancies (33%) and non-melanoma skin cancer (52%). The most common hematologic malignancy SPM is acute myeloid leukaemia (AML/MDS).

Long-term Survivorship and the "Late Effects"

The importance of caregivers has increased in recent years, especially with the changing focus in the oncology field from short term care to long term follow-up and late effects of treatment.18 Late effects of treatment (cardiac toxicity, secondary cancers, cognitive dysfunction, etc.) can appear two to 20 years after initial treatment has been completed. (19)

Physiological and Psychological Late Effects

According to a recent Norwegian study of 2024, over 83 percent (83.1%) of cancer survivors have experienced at least one late effect, with an average of 5.1 different conditions experienced by each individual.3 The three most frequently reported late effects of treatment are fatigue 59%, sleep disorder 41%. Nerve injury (38%) has also been reported among cancer survivors as a late effect.3 Cognitive impairments caused by chemotherapy have been referred to as chemo (or chemotherapy) brain and have occurred as a result of oxidative stress and chronic inflammation. (35, 36)

It is estimated that 12.5% of adult long-term survivors of childhood cancer are experiencing post-traumatic stress symptoms.2 In addition to these long term psychological sequelae, many cancer survivors also experience changes in their bodies (e.g. early menopause, lymphedema) that can complicate their psychosocial recovery. Approximately 20% of women who undergo surgery or radiation for breast cancer will experience drainage problems related to fluid accumulation or lymphedema, which can lead to significantly decreased mobility and possible increased infection risk. (37)

Table 8. Common Late Effects in Cancer Survivors