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Oncology - Treatment Toxicities - Fast Facts | NEJM Resident 360

As a resident, you will encounter patients with immediate and long-term toxicities from chemotherapy or other cancer treatment and you may be unfamiliar with the names of some cancer therapies as the number of cancer diagnoses increases. In this section, we provide examples of some common cancer therapies and the toxicities associated with these treatments.

• Generalized Treatment-Related Toxicity

• Chemotherapy

• Radiotherapy Toxicity

• Targeted-Therapy Toxicity

• Immunotherapy Toxicity

Generalized Treatment-Related Toxicity

Infertility

Patients with a history of cancer during childhood or adolescence may have to contend with long-term treatment-related toxicities. Chief among these are toxicities that affect fertility due to gonadotoxic chemotherapy, radiation (particularly targeted at the abdomen, pelvis, spine), and surgery. Studies indicate that female childhood cancer survivors are less likely to become pregnant than noncancer siblings. Associated factors include  hypothalamic/pituitary radiation, ovarian/uterine radiation, and treatment with an alkylating agent, lomustine, or cyclophosphamide. Female cancer survivors have also been reported to have 10-fold greater risk of nonsurgical premature menopause than siblings without cancer.

Risk of infertility is dependent on several factors, including type and stage of cancer; drug class and cumulative dose; radiation dose, site and number of treatments; extent of surgical therapy; and age, gender, and genetic factors. Fertility impairment can be temporary or permanent, depending on the diagnosis, stage of disease, and treatment site.

Drugs used for endocrine therapy (e.g., for breast cancer) can also be cytotoxic. The following algorithm describes techniques to preserve fertility and a framework for managing concerns in young women with breast cancer:

Treatment Guidelines for the Preservation of Fertility in Young Women with Breast Cancer

(Source: Preservation of Fertility in Patients with Cancer. N Engl J Med 2009.)

Secondary Malignancy

Survivors of childhood and adult-onset malignancies can experience secondary malignancies caused by cancer treatment as well as genetic and environmental factors. Some chemotherapy drugs, radiation therapy for some cancers, stem-cell transplantation, and combination treatment with radiation and chemotherapy are associated with the development of secondary cancer.

Chemotherapy Classes and Specific Toxicities

Different classes of chemotherapy are associated with specific side effects during the course of treatment. Some examples include:

• Taxane-based chemotherapy and other microtubule-inhibitor therapies are associated with peripheral neuropathy. For many patients, symptoms of peripheral neuropathy will improve after treatment cessation. For others, symptoms may persist and cause long-term problems with mobility and function. No consensus exists on management or prevention of peripheral neuropathy. However, recognition of the symptoms and dose adjustment may help symptom management.

• Anthracyclines and bleomycin-based regimens are associated with shortness of breath (the former can cause cardiac dysfunction and the latter can lead to pulmonary fibrosis).

• Regimens containing 5-fluorouracil (5-FU) or capecitabine are commonly associated with severe diarrhea and vomiting. In patients with dihydropyrimidine dehydrogenase (DPD) deficiency, treatment with 5-FU can lead to severe nausea, vomiting, or even death.

Chemotherapy Classes and Specific Toxicities

Class (examples)	Toxicities
Alkylating agents (chlorambucil, cyclophosphamide, ifosfamide, thiotepa, busulfan)	Hemorrhagic cystitis, encephalopathy associated with ifosfamide administration (worsened with low albumin levels)
Cytotoxic antibiotic (bleomycin)	Pulmonary fibrosis, hyperpigmentation, dermatographism, fever (during infusion)
Antimetabolites (5-fluorouracil, capecitabine, methotrexate, cytarabine)	Diarrhea, mucositis, hand–foot syndrome, coronary artery spasm
Anthracyclines (epirubicin, doxorubicin)	Cardiovascular toxicity (see table below)
Vinca alkaloids (vincristine, vinblastine)	Peripheral neuropathy
Taxanes (paclitaxel)	Peripheral neuropathy, joint pain
Platinum-based (cisplatin, carboplatin, oxaliplatin)	Renal dysfunction
Topoisomerase inhibitors (etoposide, topotecan)	Asthenia, stomatitis, diarrhea

Radiotherapy Toxicity

Radiotherapy is used in both curative- and palliative-care settings, and associated toxicities vary. Radiation therapy can lead to genomic instability through creation of double-stranded breaks in DNA that can spur malignant transformation. Radiotherapy is thought to contribute to about 5% of the total treatment-related secondary malignancies.

• Immediate toxicity may include skin changes at the radiation site, nausea, vomiting, and diarrhea, depending on the location of radiotherapy.

• Radiotherapy to the brain can result in nausea, cognitive impairment (long-term and temporary), and alopecia.

• Pediatric and young-adult cancer patients can experience infertility as ovaries and testicles are sensitive to the effects of radiation.

Biological Effects and Normal Tissue Toxicity After Radiotherapy

(Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer. The Tumour Microenvironment After Radiotherapy: Mechanisms of Resistance and Recurrence, copyright 2015.)

Targeted-Therapy Toxicity

Antibody therapy: Although conventional chemotherapy and radiotherapy have had some success in attacking malignant cells, the ability to selectively target tumor cells is limited. Advances in drug design have attempted to circumvent this issue by development of drugs through use of monoclonal antibodies.

• Monoclonal antibodies (e.g., rituximab, trastuzumab, and cetuximab) have been included in regimens for many types of cancer, ranging from breast cancer to lymphomas and colorectal cancer.

  • Patients may have allergic reactions during an infusion with monoclonal antibodies. Management guidelines vary by institution, but antihistamines, glucocorticoids, and fluids can be started depending on the severity of these reactions.

  • Some monoclonal antibodies (e.g., rituximab) can cause long-term changes in immunoglobulin levels that lead to an increased risk of infections.

  • Some monoclonal antibodies (e.g., rituximab) can cause cytokine release syndrome (CRS), which is an acute systemic inflammatory syndrome characterized by hypothermia or fever, hypotension, rash, and multiple organ dysfunction.

  • Trastuzumab can be associated with heart failure during treatment. Therefore, regular echocardiograms should be requested. Patients with a history of trastuzumab exposure may develop long-term cardiac dysfunction.

  • Bevacizumab is an antiangiogenic monoclonal antibody associated with high blood pressure, venous thromboembolism, and bleeding.

Tyrosine kinase inhibitors (e.g., erlotinib, lapatinib, sorafenib, sunitinib) are CYP3A4 substrates that can interact with other drugs, and some interactions can lead to reduced drug efficacy (something to consider when prescribing).

• Tyrosine kinase inhibitors are also associated with dermatological changes that may require intervention with glucocorticoid or antibiotic creams.

• Some drugs in this class (e.g., sorafenib and sunitinib) that target multiple receptors can lead to hypertension and diarrhea.

• Tyrosine kinase inhibitors can also affect thyroid function.

Mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus, temsirolimus):

• The most common toxic effects are mucositis and skin toxicity.

• Other toxicities include diarrhea, nausea, and loss of appetite.

• Patients may also experience short-term shortness of breath caused by pulmonary fibrosis.

Cardiovascular toxicities associated with targeted cancer therapies are summarized in the following table:

(Source: Cardiovascular Toxic Effects of Targeted Cancer Therapies. N Engl J Med 2016.)

Immunotherapy Toxicity

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, ipilimumab) are increasingly used for treatment of a variety of tumor types. The safety profile of immune checkpoint inhibitors is comparable to that of traditional chemotherapeutic agents.

• Immune-related adverse events: Most adverse effects associated with inflammation caused by immune checkpoint blockade are reversible, and death due to these events is infrequent. Adverse events usually occur within weeks or months of initiating therapy but can occur anytime, even after treatment discontinuation. The following figure demonstrates the spectrum of immune-related adverse events associated with immune checkpoint inhibitors.

Organs Affected by Immune Checkpoint Blockade

(Source:Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018.)

• Treatment of immune-related adverse events: In most cases, immunosuppression with glucocorticoids is the first-line treatment. Infliximab, an antibody against tumor necrosis factor (TNF) alpha, is considered second-line treatment.

• Retreatment of immune-related adverse events: The safety of retreatment with an immune checkpoint inhibitor after an adverse event depends on the severity of the initial adverse event. Adverse events may not necessarily recur after a switch in class of immune checkpoint inhibitor therapy.

The following figure demonstrates an example of signaling pathways in a tumor microenvironment that could be targeted by immune checkpoint Inhibitors.

Inhibition of Tumor-Specific T-cell Function by the Expression of PD-1 and Its Ligands in the Tumor Microenvironment

(Source: Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med 2016.)

CAR T-cell and BiTE Immunotherapy

Although traditional antibody therapy targets cells with high replication rates, the biggest drawback is that it fails to distinguish malignant cells from normal cells that replicate under physiologic conditions (e.g., epidermal or hematologic cells), and therefore, considerably increase the risk of adverse effects. Given the unparalleled ability of immune cells to recognize antigens displayed on the surface of pathogens, researchers are increasingly interested in finding ways to harness the body’s own ability to attack tumor cells. Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) therapy are two examples.

CAR T-cell therapy: CAR T-cell therapy employs an individual’s own genetically engineered cytotoxic T cells to attack malignant tumor cells. Currently this modality is primarily used for hematologic malignancies (most often B-cell malignancies) and has changed the management of relapsed and refractory cancers. CAR T-cell therapy is also being studied for treatment of solid-tumor malignancies.

Bispecific T-cell engager (BiTE) therapy**:** BiTE therapy uses endogenous T cells to attack antigens expressed on malignant cells to eliminate cancer. Unlike CAR T-cell therapy, this modality eliminates the need to create genetically altered T cells and the issues that come with that (ex vivo expansion and manipulation).

• BiTE molecules consist of two binding domains:

• • One recognizes tumor-expressed antigen (e.g., CD19).

  • Another recognizes CD3 on cytotoxic T cells.

• When a BiTE molecule engages both a cytotoxic T cell and a tumor cell, the T cells begin proliferating and subsequently malignant lysis occurs.

• Blinatumomab was the first approved BiTE-molecule therapy for acute lymphoblastic leukemia (ALL); it targets CD19 surface antigens on B cells. Additional BiTE molecules in development target other hematologic malignancies (e.g., multiple myeloma, acute myeloid leukemia, and B-cell non-Hodgkin lymphoma) and solid tumors (e.g., prostate cancer, glioblastoma, gastric cancer, and small-cell lung cancer).

Mechanism of Action for Bispecific T-Cell Engager (BiTE)

(Source: The BiTE (Bispecific T-cell Engager) Platform: Development and Future Potential of a Targeted Immuno-oncology Therapy Across Tumor Types. Cancer 2020.)

**(Source: CAR-T Cells and BiTEs in Solid Tumors: Challenges and Perspectives. J Hematol Oncol 2021.)**Challenges and Toxicity

• Tumor-antigen specificity: Some challenges faced by both BiTE therapy and CAR T-cell therapy include the development of tumor-antigen specificity. Many antigens found in solid tumors lack specificity and are often found at low levels in normal tissue, thereby limiting their use to this disease group. In addition, heterogenous expression of the target antigen (e.g., between different regions of a tumor) may limit the efficacy of these novel therapies. Also of note, many solid tumors have harsher tumor microenvironments, which can render these therapies dysfunctional.

• Cytokine release syndrome: CRS is a rapid immune reaction that develops soon after administration of the agent and activates the massive release of cytokines (e.g., interferon gamma [IFN-γ] and interleukin-6 [IL-6]) from targeting cancer cells, leading to a life-threatening range of neurotoxic and pneumotoxic symptoms. Vasodilation with capillary leak and edema can result in severe fluid refractory shock that requires vasoactive support to maintain organ perfusion.

  • Clinical and laboratory manifestations of CRS are similar to manifestations of hemophagocytic lymphohistiocytosis or macrophage activation syndrome, including cytopenia, hepatosplenomegaly, coagulopathy, and hyperferritinemia.

  • Symptoms of CRS include hypothermia or fever, hypotension, rash, and multiple organ dysfunctio In patients with signs and symptoms of potential CRS (e.g., fever), close observation of fever and inflammatory markers is warranted, including C-reactive protein (CRP) and ferritin. Mild-to-moderate CRS symptoms can spontaneously resolve with supportive care (e.g., antipyretics and intravenous fluids). Refractory hypotension necessitates admission to an intensive care unit and treatment with vasoactives and cytokine blockade with tocilizumab. If patients do not improve on tocilizumab, treatment with escalating intravenous methylprednisolone therapy is warranted. In refractory cases, immunosuppressants (e.g., cyclophosphamide) might be of benefit.

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