The following cases and commentary, which focus on oncology, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 17).
Case 1: Breast cancer and a fall
An 80-year-old woman is hospitalized after a mechanical fall. She has a history of stage I estrogen receptor–positive and progesterone receptor–positive left breast cancer diagnosed 13 years ago; HER2 testing was not done at that time. She was treated with breast-conserving surgery, primary breast radiation, and adjuvant tamoxifen for 5 years. She is not having any current bone pain or headaches.
On physical examination, vital signs are normal. A large palpable lesion is present over the left frontal skull. There is no lymphadenopathy. Examination of the left breast shows a healed incision with no masses. There are no right breast masses. The remainder of the examination is unremarkable.
Serum alkaline phosphatase level is elevated at 264 U/L (normal 36-92 U/L) and serum CA 15-3 level is 100.2 U/mL (normal <30 U/mL). Remaining laboratory studies, including serum calcium level, are normal.
CT scan of the head done in the emergency room shows a 3-cm lytic lesion in the left frontal skull. MRI of the brain confirms the presence of a large frontal skull lesion but shows no brain metastases. Bone and CT scans show lesions in the spine, skull, sternum, and bilateral ilium bones consistent with metastases. No visceral disease is present.
Biopsy of a lytic lesion in the right ilium shows metastatic adenocarcinoma consistent with primary breast cancer (estrogen receptor positive, progesterone receptor positive, and HER2 negative).
Which of the following is the most appropriate treatment?
C. Radiation to areas of bone involvement
D. Radium-223 isotope
Case 2: Leg weakness
A 78-year-old man is hospitalized for a 1-week history of progressive and severe back pain and weakness in both legs. He describes a sense of “heaviness” in his legs and has had increasing difficulty climbing stairs and getting out of a chair. Medical history is significant for asymptomatic multiple myeloma that has been followed with periodic examinations and laboratory studies; his last assessment was 3 months ago and was stable.
On physical examination, vital signs are normal. He has point tenderness over the T10 and T11 vertebral bodies, decreased lower extremity muscle strength (3+/5), increased reflexes isolated to both lower extremities, and bilateral extensor plantar responses. The remainder of the physical examination is unremarkable.
Laboratory studies are significant for a serum hemoglobin level of 6.5 g/dL (65 g/L) and a serum calcium level of 13 mg/dL (3.2 mmol/L).
MRI of the thoracic and lumbar spine shows a vertebral body mass with extension into the epidural space at T12 and compression of the spinal cord.
Which of the following is the most appropriate initial step in treatment?
A. Biopsy of the epidural mass
B. Decompressive surgery
C. Intravenous glucocorticoids
D. Multiagent chemotherapy
E. Radiation therapy
Case 3: Diarrhea on ipilimumab
A 55-year-old woman is evaluated in the emergency department for a 3-day history of diarrhea. She reports seven to eight stools daily without vomiting. She also notes abdominal cramping without vomiting and has been able to maintain adequate fluid intake. Medical history is significant for metastatic malignant melanoma, for which she recently completed the third of four planned doses of ipilimumab therapy. She has no history of inflammatory bowel disease, recent antibiotic use, recent travel, or consumption of uncooked foods. The remainder of the medical history is noncontributory, and she takes no other medications.
On physical examination, temperature is 37.5 °C (99.5 °F), blood pressure is 125/85 mm Hg, pulse rate is 90/min without orthostatic changes, and respiration rate is 14/min. The abdomen is soft and nontender with increased bowel sounds. The remainder of the physical examination is normal.
Laboratory studies show hemoglobin 12.2 g/dL (122 g/L), leukocyte count 9300/μL (9.3 × 109/L) with normal differential, alanine aminotransferase 120 U/L, aspartate aminotransferase 160 U/L, and creatinine 1.2 mg/dL (106.1 μmol/L). Fecal occult blood testing is negative.
A chest radiograph is normal and abdominal films show nondilated bowel loops with no free air.
In addition to discontinuing the ipilimumab and providing supportive care, which of the following is the most appropriate next step in treatment?
A. Broad-spectrum intravenous antibiotics
B. Granulocyte-macrophage colony-stimulating factor
C. High-dose intravenous glucocorticoids
Case 4: Cancer diagnosis and poor performance score
A 70-year-old man is hospitalized for new-onset abdominal pain and nausea. He has had little to eat or drink for the past 24 hours. The patient had a cerebrovascular accident 1 year ago and since then has resided in a nursing home. He has long-standing congestive cardiomyopathy, hypertension, type 1 diabetes mellitus with peripheral neuropathy, and chronic kidney disease. He is mostly bedbound but is able to sit in a chair with assistance for several hours each day. Medications are amlodipine, enalapril, furosemide, insulin, and metoprolol.
On physical examination, the patient appears chronically ill. Temperature is 37.7 °C (99.9 °F), blood pressure is 150/85 mm Hg, pulse rate is 80/min, and respiration rate is 12/min. BMI is 21. The sclerae are icteric, and mucous membranes are dry. There are crackles at the bilateral lung bases. Heart examination is significant for an S3 heart sound. The abdomen is moderately distended with diffuse mild tenderness but without rebound or guarding. The liver edge is palpable. There is bilateral pitting edema of the extremities.
The patient's Eastern Cooperative Oncology Group/World Health Organization performance status level is assessed to be 4 (completely disabled, totally confined to a bed or chair, and unable to do any self-care).
The serum albumin level is 2.8 g/dL (28 g/L), the serum total bilirubin level is 2.3 mg/dL (39.3 μmol/L), and the serum creatinine level is 2.6 mg/dL (229.8 μmol/L).
A CT scan of the abdomen without contrast shows hepatomegaly with multiple metastatic lesions, enlarged retroperitoneal lymph nodes, abdominal carcinomatosis, moderate ascites, and a nonobstructing mass lesion in the cecum. A diagnostic paracentesis is performed, and 2 liters of bloody ascitic fluid are removed; cytology samples are positive for adenocarcinoma.
Gentle intravenous hydration is begun, and the patient is given parenteral morphine, which provides adequate relief of pain.
Which of the following is the most appropriate management?
A. Leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX)
B. Single-agent, low-dose 5-fluorouracil
C. Surgical resection of the cecal mass
D. Supportive, comfort-oriented care
Case 5: Multiple myeloma
A 68-year-old woman is evaluated in the emergency department for a 1-week history of polyuria, polydipsia, and progressive confusion. She has a 2-year history of multiple myeloma that was treated 1 year ago with chemotherapy. Her medical history is otherwise noncontributory, and she takes no medications.
On physical examination, the patient is afebrile, blood pressure is 100/60 mm Hg, pulse rate is 100/min, and respiration rate is 14/min. The patient's skin and mucous membranes are dry. She appears confused, and her reflexes are hyporeactive. The remainder of her examination is unremarkable.
Laboratory studies show blood urea nitrogen 60 mg/dL (21.4 mmol/L), calcium 14.5 mg/dL (3.6 mmol/L), creatinine 3.5 mg/dL (309.4 μmol/L) from baseline of 1.2 mg/dL (106.1 μmol/L).
Intravenous high-volume normal saline and high-dose glucocorticoids are started.
Which of the following is the most appropriate next step in treatment?
C. Intravenous bisphosphonate
D. Multiagent chemotherapy
Answers and commentary
Correct answer: A. Anastrozole.
Because this patient's metastases involve only bone, her cancer is estrogen receptor positive, and she has had a long disease-free interval, she has a high likelihood of responding to primary antiestrogen therapy with anastrozole. Other aromatase inhibitors such as letrozole or exemestane would be equally effective. Aromatase inhibitors are superior to tamoxifen for first-line treatment of metastatic breast cancer because of improved response rates and disease-free survival. If she becomes resistant to aromatase inhibitor therapy, everolimus is a mammalian target of rapamycin (mTOR) inhibitor that is approved for treatment of metastatic breast cancer in combination with exemestane. If she responds to anastrozole and subsequently develops progressive disease, other antiestrogen agents, including tamoxifen and fulvestrant, could be used sequentially.
Chemotherapy with agents such as paclitaxel is used instead of antiestrogen therapy for treatment of metastatic breast cancer in patients with hormone receptor–negative disease, those with an impending visceral crisis due to extensive metastases, or those who do not respond to antiestrogen therapy.
Radiation to symptomatic areas of bone metastases is an important palliative treatment. However, patients with asymptomatic or minimally symptomatic bone lesions are not treated with radiation therapy unless bone stability is a concern.
Radium-223 is an alpha particle–emitting isotope that targets bone metastases. It is only used in bone metastases due to castrate-resistant prostate cancer.
- Patients with estrogen receptor–positive breast cancer who develop metastases limited to bone after a long disease-free interval should be treated initially with an aromatase inhibitor.
Correct answer: C. Intravenous glucocorticoids.
This patient with spinal cord compression should receive immediate administration of intravenous high-dose glucocorticoids to prevent permanent neurologic deficits. This patient has MRI-confirmed spinal cord compression characterized by mid back pain and physical findings of lower extremity hyperreflexia and weakness. His known multiple myeloma with corresponding anemia and hypercalcemia suggest progression of his disease with a plasma cell tumor as the cause of his spinal cord compression. Glucocorticoid therapy is the initial treatment in most cases of malignant spinal cord compression as they decrease inflammation and reduce the mass effect due to edema associated with many tumors. In this case, glucocorticoid therapy has the added benefit of directly treating the hypercalcemia and plasma cell myeloma. Glucocorticoid treatment is then followed with more definitive therapy, often radiation and possible neurosurgical intervention in some cases.
Biopsy of the epidural mass is not necessary because of the patient's known likely causative disease and could delay initiation of glucocorticoids and radiation therapy and increase the risk of permanent nerve damage.
Although neurosurgical intervention consisting of decompressive surgery might be necessary in some patients with spinal cord compression, it would not be appropriate before administration of immediate glucocorticoids.
Definitive treatment with chemotherapy or an immunomodulator may be appropriate but would not have the required immediate effect of glucocorticoids in preventing progressive neurologic damage.
Radiation therapy alone would not address the swelling associated with spinal cord compression nor the hypercalcemia or underlying systemic plasma cell myeloma. However, radiation therapy is often a useful therapy for treating bulky disease.
- Patients with cancer who develop symptoms of possible spinal cord compression require immediate administration of intravenous high-dose glucocorticoids to prevent permanent neurologic deficits.
Correct answer: C. High-dose intravenous glucocorticoids.
Initiation of high-dose intravenous glucocorticoids and aggressive supportive care in addition to discontinuing the offending medication is the most appropriate treatment for this patient with ipilimumab toxicity with severe diarrhea and evidence of autoimmune hepatitis. Ipilimumab is a new class of antineoplastic therapy that inhibits the function of T-cell checkpoint receptors (ipilimumab or PD-1 and PD-L1 inhibitors), thereby enhancing the function of the immune system and inducing remissions in patients with various solid tumors, particularly metastatic melanoma. However, T-cell checkpoint inhibitors also can cause many potentially permanent and life-threatening organ toxicities that are autoimmune-mediated based on their enhancement of immune function. These include dermatologic (rash, mucositis), gastrointestinal (diarrhea, colitis), liver (autoimmune hepatitis), and endocrine (hypothalamic/pituitary, thyroid, and adrenal insufficiency). Other organ involvement (eye, kidney, hematologic, pulmonary, and neurologic) has also been reported. Because the toxicity results from triggering an exaggerated immune response, treatment of these toxicities involves removing the causative agent and providing immunosuppression, preferably with high-dose glucocorticoids due to their nonspecific immune-suppressing effects and rapid onset of action. Recognition of the autoimmune effect of the treatment is critical since the autoimmune-triggered toxicity from this class of medications can be fatal if immunosuppressive therapy is delayed.
Because the mechanism of toxicity is not directly related to leukopenia and this patient has a normal leukocyte count with no objective evidence of infection, broad-spectrum antibiotics are not indicated, and delayed recognition of the drug-related syndrome from treatment of possible bacterial infection could be detrimental.
Similarly, because the toxicity of T-cell checkpoint inhibitors is not due to leukopenia, treatment with growth factors, such as granulocyte-macrophage colony-stimulating factor, does not have a role in either the prevention or treatment of complications associated with this class of drugs.
Because rapid immunosuppression may reverse the severe autoimmune reactions triggered by ipilimumab, discontinuation of the medication and supportive care alone is inadequate therapy for this patient.
- Patients with acute ipilimumab toxicity should receive fluid replacement and immediate glucocorticoid therapy to reverse the damage this agent can cause; delay in treatment can be fatal.
Correct answer: D. Supportive, comfort-oriented care.
Supportive, comfort-oriented care is most appropriate for this patient who has advanced metastatic adenocarcinoma in the setting of multiple severe chronic comorbidities and a debilitated medical condition resulting in a poor performance status. A key aspect of managing patients with cancer is an assessment of their performance status, defined as the specific level of well-being and ability to perform daily activities. Several formal measures of performance status are available, such as the Karnofsky score and the Zubrod score (also called the Eastern Cooperative Oncology Group/World Health Organization system). Scores on these measures correlate with the ability of an individual patient to tolerate potential therapeutic interventions. In patients with very low performance measure scores, a less aggressive and more supportive treatment approach is usually warranted based on likely outcomes of therapy. Virtually all oncology clinical trials showing efficacy of chemotherapy exclude patients with poor performance status because toxicity and harm occur more frequently and clinical benefit occurs less frequently in these patients. In addition, this patient has elevated serum bilirubin and creatinine levels. Because liver and kidney function affect metabolism of many oncology drugs, treatment of patients with chronic liver or kidney disease is challenging and is associated with a higher risk of complications. In some cases, poor performance has developed based on tumor-related symptoms and might be expected to improve with treatment of the cancer. However, this patient's poor performance status appears to be due to his chronic illnesses and is not likely to improve significantly following treatment of his cancer.
Combination chemotherapy is contraindicated in a debilitated patient and would likely cause severe and even life-threatening toxicity.
Single-agent, low-dose chemotherapy is highly unlikely to provide any benefit and is still associated with the risk of toxicity.
The patient is a poor candidate for surgery, has no evidence of colonic obstruction, and would likely have considerable postoperative and healing complications with little, if any, chance of benefit.
- Supportive, comfort-oriented care is appropriate for a frail patient with metastatic cancer, significant medical comorbidities, and a poor performance status.
Correct answer: C. Intravenous bisphosphonate.
The most appropriate next step in treatment for this patient with malignancy-associated hypercalcemia is an intravenous bisphosphonate. Initial therapy for hypercalcemia is high-volume normal saline hydration, and in those with kidney failure, forced diuresis with a loop diuretic such as furosemide. This helps restore intravascular volume and decreases serum calcium levels acutely. For tumors that are glucocorticoid-sensitive, such as multiple myeloma and some types of lymphoma, glucocorticoids are indicated to decrease tumor-associated osteoclast activation. Bisphosphonates are powerful inhibitors of osteoclast-mediated bone resorption with an onset of effect occurring several days after administration and a duration of up to several weeks depending on the specific agent used, which allows longer-term control of calcium levels. Hypercalcemia is usually a manifestation of advanced disease, is associated with poor prognosis, and occurs in up to 10% of patients with cancer. Hypercalcemia is most common among patients with multiple myeloma and breast, renal, and lung cancer. Patients initially present with nausea, vomiting, constipation, and polyuria. Polydipsia, diffuse muscle weakness, and confusion follow.
Cinacalcet is a calcimimetic agent that is used to lower the calcium level in patients with primary and tertiary hyperparathyroidism associated with chronic kidney disease. It is not effective or approved for use in malignancy-associated hypercalcemia.
Dialysis is an effective method for lowering serum calcium levels, although it is generally reserved for patients with severe, symptomatic hypercalcemia who have not responded to acute treatment with hydration and other measures or patients in whom aggressive hydration is contraindicated. Dialysis would not be appropriate in this patient whose response to hydration and other initial therapies has not been assessed.
Treatment with chemotherapy or disease-specific targeted agents would be appropriate for long-term control of hypercalcemia but would not be effective for short-term therapy of hypercalcemia.
- Immediate hydration with large-volume normal saline infusion, forced diuresis with furosemide, glucocorticoid therapy for glucocorticoid-responsive malignancies such as multiple myeloma, and a bisphosphonate is appropriate treatment of malignancy-related hypercalcemia.