Cancer Chemotherapy: Keys to Diagnosing Common Toxicities

Patients receiving chemotherapy for cancer treatment are likely to encounter a range of toxicities. For example, this image shows massive dilatation of the colon, especially the right colon and cecum, secondary to ileus. Such gastrointestinal autonomic dysfunction—often manifesting as bloating, constipation, ileus, and abdominal pain—may complicate vincristine-containing therapy. Patients who develop such complications may require modifications of chemotherapy dosage. Can you recognize the complications of chemotherapy presented in the following cases?

A 65-year-old man with stage IV non-small cell lung cancer presents with fatigue, rash, and dark urine. He is currently undergoing chemotherapy with gemcitabine and carboplatin. Physical examination reveals conjunctival pallor and a bilateral lower-extremity petechial rash. The patient's peripheral blood smear is shown. Pertinent laboratory findings include the following measurements: hemoglobin 8.0 g/dL, platelet count 15 × 10⁹/L, creatinine 3.1 mg/dL, lactate dehydrogenase 1,200 U/L (normal: <600 U/L), haptoglobin 15 mg/dL, prothrombin time 12 s (normal: 10-13 s), and activated partial thromboplastin time 30 s (normal: 27-39 s). What is the most likely diagnosis?

1. Immune thrombocytopenic purpura
2. Thrombotic thrombocytopenic purpura
3. Sickle cell crisis
4. Disseminated intravascular coagulation

Image courtesy of Yuri Fedoriw, MD.

Answer: Thrombotic thrombocytopenic purpura

The peripheral blood smear shown reveals schistocytes (red arrows) and thrombocytopenia. The presence of microangiopathic hemolytic anemia, renal impairment, and thrombocytopenia is suggestive of thrombotic thrombocytopenic purpura (TTP). Chemotherapy drugs such as gemcitabine and mitomycin have been reported to cause secondary TTP, which is thought to arise from different pathophysiologic mechanisms than idiopathic TTP (caused by decreased levels of the enzyme ADAMTS13). Clopidogrel, bone marrow transplantation, and pregnancy also can precipitate TTP. If secondary TTP is suspected, the offending drug should be discontinued.

Image courtesy of Yuri Fedoriw, MD.

A 19-year-old woman presents with worsening bilateral hip pain (right worse than left) for the past month. She has acute lymphoblastic leukemia and is currently undergoing maintenance chemotherapy every 3 months with vincristine, prednisone, mercaptopurine, and methotrexate. What is the most likely cause of the patient's bilateral hip pain?

1. Osteoarthritis of the hip
2. Trochanteric bursitis
3. Avascular necrosis of the femoral head
4. Osteomyelitis

Answer: C. Avascular necrosis of the femoral head

Avascular necrosis (AVN) of the femoral head is a known complication in patients receiving high-dose steroids as part of their chemotherapy. The anterolateral aspect of the femoral head is the most vulnerable site for development of AVN due to the degree of load-bearing on this structure. Magnetic resonance imaging (MRI) of the hip (shown) is the most sensitive means of diagnosing AVN (arrows). Although AVN is usually bilateral, the onset in each hip can occur separately, with progression at different rates.

A 55-year-old woman with stage IV estrogen receptor-positive breast cancer with bone metastasis presents with left maxillary pain, swelling, and halitosis. She is currently on anastrozole (an aromatase inhibitor) and monthly zoledronic acid for prevention of bone metastasis-related complications. In view of the physical examination finding shown, what is the most likely diagnosis?

1. Salivary gland neoplasm
2. Osteomyelitis
3. Squamous cell carcinoma of the hard palate
4. Osteonecrosis of the jaw

Answer: D. Osteonecrosis of the jaw

Osteonecrosis of the jaw is associated with high-dose bisphosphonate use in patients with cancer, particularly those who have had recent dental extractions. Bisphosphonates inhibit osteoclasts as well as prevent osteoblast apoptosis, resulting in decreased bone turnover and inhibition of the bone's reparative ability, which are thought to be responsible for this complication. The previous image showed exposed necrotic bone in the left anterior maxilla. This dental panoramic radiograph shows a moth-eaten appearance of the right mandibular angle area (arrow) and an unhealed extraction socket.

A 62-year-old man with colorectal cancer is currently undergoing chemotherapy with capecitabine and oxaliplatin. He presents with gradual bilateral development of pain, redness, numbness, and desquamation of his palms (shown). What is the most likely diagnosis?

1. Stevens-Johnson syndrome
2. Psoriasis
3. Palmar-plantar erythrodysesthesia
4. Toxic shock syndrome

Image courtesy of Wikimedia Commons.

Answer: Palmar-plantar erythrodysesthesia

Palmar-plantar erythrodysesthesia, also known as hand-foot syndrome, is an adverse drug reaction commonly associated with chemotherapy drugs such as capecitabine, fluorouracil, or docetaxel. This condition usually starts as a tingling or numb sensation of the palms and soles, which then evolves into painful, well-demarcated swelling and plaques with skin desquamation. Symptoms usually resolve within 1–2 weeks after discontinuance of the offending chemotherapy agent. In patients with mild symptoms, pyridoxine has been used to help relieve symptoms to allow continuation of chemotherapy;^[1] however, there is evidence that pyridoxine may not be effective in patients treated with capecitabine for palmar-plantar erythrodysesthesia.^[2]

Image courtesy of Winston Tan, MD, FACP.

A 32-year-old man with testicular cancer completed 3 cycles of chemotherapy with bleomycin, etoposide, and cisplatin 3 months ago. He presents with a complaint of exertional dyspnea of recent onset. His chest radiograph is shown. What is the most likely diagnosis?

1. Pulmonary edema
2. Pulmonary fibrosis
3. Multilobar pneumonia
4. Pulmonary hemorrhage

Answer: B. Pulmonary fibrosis

The previous chest radiograph showed scattered reticular opacities, whereas this high-resolution computed tomography (CT) scan of the lung shows extensive pulmonary fibrosis, likely induced by bleomycin. Chemotherapy drugs such as bleomycin, busulfan, and methotrexate are known to cause lung toxicity, which can result in interstitial pneumonitis and fibrosis, hypersensitivity reaction, acute respiratory distress syndrome, cryptogenic organizing pneumonia, or bronchiolitis obliterans organizing pneumonia. Pulmonary fibrosis should be suspected in patients receiving one or more chemotherapy drugs known to cause lung toxicity and who have corresponding radiologic findings.

Image courtesy of Wikimedia Commons.

A 40-year-old man with metastatic colorectal cancer is currently receiving chemotherapy with irinotecan, oxaliplatin, and 5-fluorouracil (5-FU). He reports oral pain and difficulty swallowing. Physical examination of his oral cavity is shown. What is the most likely diagnosis?

1. Oral candidiasis
2. Herpes simplex
3. Mucositis
4. Herpes zoster

Answer: C. Mucositis

The previous image revealed an erythematous oral mucositis lesion on the buccal mucosa, whereas this image demonstrates ulcerative oral mucositis. Chemotherapeutic agents such as 5-FU have a known association with oral mucositis that is thought to involve molecular, cellular, and tissue-based changes; there is increasing evidence that genetic susceptibility may play a role.^[3] This condition can greatly affect the patient's quality of life due to severe pain and restriction of oral intake. Oral mucositis is usually self-limiting and resolves approximately 2–4 weeks after completion of chemotherapy.^[3] Appropriate mouth care using a saline rinse not only helps to soothe the inflamed/ulcerated mucosa but also keeps the mucosa moist.

A 32-year-old man with acute myeloid leukemia (AML) in complete remission underwent an allogeneic peripheral blood stem cell transplantation 7 days ago. He is currently on an intravenous antibiotic, doripenem, for neutropenic fever and is also receiving tacrolimus for prevention of graft-versus-host disease. For the past 2 days, his blood pressure has been elevated, averaging 170/95 mm Hg. He was witnessed having a generalized tonic-clonic seizure, which resolved spontaneously. An urgent MRI of the brain was obtained (shown). What is the most likely diagnosis?

1. Hemorrhagic stroke
2. Ischemic stroke
3. Posterior reversible encephalopathy syndrome
4. Chloroma (leukemic infiltration of the brain)

Image courtesy of Wikimedia Commons.

Answer: C. Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome can occur due to the administration of drugs such as tacrolimus and cyclosporine, which are commonly used in patients undergoing hematopoietic stem cell transplantation. Patients can present with headaches, hypertension, confusion, vision loss, and sometimes seizures. The diagnosis is typically made on MRI of the brain, which reveals hyperintensities on T2-weighted imaging, as in this image that reveals multiple corticosubcortical areas of T2-weighted hyperintense (white) signal involving the bilateral occipital and parietal lobes (arrows) and the pons.

Image courtesy of Wikimedia Commons.

A 56-year-old woman presents with a 3-month history of fatigue and exertional dyspnea. She has a history of breast cancer and completed 4 cycles of chemotherapy with doxorubicin and cyclophosphamide 5 years ago. Physical examination is significant for conjunctival pallor. A complete blood count reveals hemoglobin of 7.1 g/dL, mean corpuscular volume of 112 fL, white blood cell count of 2.9 × 10⁹/L with 33% neutrophils, and a platelet count of 88 × 10⁹/L. Her peripheral blood smear is shown. What is the most likely diagnosis?

1. Aplastic anemia
2. Paroxysmal nocturnal hemoglobinuria
3. Myelodysplastic syndrome
4. Vitamin B12 deficiency

Image courtesy of Yuri Fedoriw, MD.

Answer: C. Myelodysplastic syndrome

The peripheral blood smear reveals a hypolobulated neutrophil (known as a pseudo Pelger-Huët cell or Pelger-Huët anomaly), oval macrocytic red blood cells (RBCs), and giant platelets, all of which are commonly seen in patients with myelodysplastic syndrome (MDS). MDS can occur after treatment for another malignancy, particularly if an alkylating agent (eg, cyclophosphamide, busulfan, melphalan) was part of the chemotherapy regimen. The latency period for MDS arising after alkylating agent therapy is typically 3–7 years.

Image courtesy of Yuri Fedoriw, MD.

A 68-year-old man is currently undergoing chemotherapy for multiple myeloma with cyclophosphamide, bortezomib, and dexamethasone. He presents with a 3-day history of a painful vesicular rash on the upper abdomen. What is the most likely diagnosis?

1. Impetigo
2. Herpes zoster reactivation
3. Candidal intertrigo
4. Tinea corporis

Answer: B. Herpes zoster reactivation

The previous image revealed a cluster of vesicular lesions on an erythematous base, which is a classic presentation of herpes zoster reactivation. The distribution of zoster is usually dermatomal, as shown here. Herpes zoster is common in patients receiving high-dose corticosteroids. However, there is increasing evidence that bortezomib-based therapy for multiple myeloma itself is a risk factor for herpes zoster reactivation.^[4,5] The mechanism by which bortezomib increases reactivation of herpes zoster is not well understood. Antiviral prophylaxis has been found effective for preventing these reactivations.^[5,6]

A 45-year-old man who was recently diagnosed with multiple myeloma presents with acute shortness of breath. His current chemotherapy regimen includes melphalan, prednisone, and lenalidomide. He underwent a ventilation-perfusion scan (shown). On the basis of his clinical history, presentation, and findings, what is the most likely diagnosis?

1. Pulmonary embolism
2. Chronic obstructive pulmonary disease
3. Postlobectomy of the left upper lobe
4. Left lobar pneumonia

Answer: A. Pulmonary embolism

The ventilation-perfusion scan revealed a perfusion defect in the left upper quadrant that is suggestive of pulmonary embolism, whereas a CT scan of the chest demonstrated a saddle pulmonary embolism (shown). Patients with newly diagnosed or previously treated multiple myeloma receiving thalidomide- or lenalidomide-based regimens in combination with dexamethasone are at increased risk for venous thromboembolism.^[7] The American Society of Clinical Oncology recommends that these high-risk patients receive venous thromboembolism prophylaxis.^[8]

A 55-year-old black man recently diagnosed with AML is currently undergoing induction chemotherapy. One day after he received rasburicase for the prevention of tumor lysis syndrome, his hemoglobin level dropped from 11.1 g/dL to 6.2 g/dL. Pertinent laboratory findings include the following results: lactate dehydrogenase 1,900 U/L (normal <600 U/L), haptoglobin 10 mg/dL, and total bilirubin 3.0 mg/dL. His peripheral blood smear is shown. What is the most likely diagnosis?

1. Sickle cell anemia
2. Glucose-6-phosphate dehydrogenase deficiency
3. Hereditary spherocytosis
4. Autoimmune hemolytic anemia

Answer: B. Glucose-6-phosphate dehydrogenase deficiency

The peripheral blood smear demonstrates spherocytes, which are suggestive of acute hemolysis, and bite cells (arrows), which are pathognomonic of glucose-6-phosphate dehydrogenase (G6PD) deficiency. The disease is inherited as an X-linked disorder, with the highest prevalence among persons of African, Asian, or Mediterranean descent. When patients with G6PD deficiency are exposed to oxidative drugs such as rasburicase, dapsone, or sulfonamides, the RBCs undergo rapid hemolysis under stress. Thus, it is important to consider assays for G6PD enzyme activity in high-risk populations prior to starting medications known to exacerbate G6PD deficiency.

Image courtesy of Yuri Fedoriw, MD.