Published in the March 2013 issue of Today’s Hospitalist
ONGOING ADVANCES in cancer treatment mean that many patients are living longer. But as both the number and intensity of treatment cycles increase, so do side effects.
Hospitalists are now more likely to encounter new admissions with hem/onc emergencies due to either the side effects of therapy or worsening disease, or both. And given the movement toward self-administered oral chemotherapy agents, patients in trouble may not show up at the hospital until they’re very ill.
At a conference on the management of hospitalized patients held last fall at the University of California, San Francisco, J. Ben Davoren, MD, PhD, an oncologist at the San Francisco VA Medical Center, discussed some common emergencies that arise in very ill, extensively treated patients. Those include cord compression and other CNS-metastasis problems, as well as hypercalcemia and neutropenic fever.
When setting treatment priorities for such patients, Dr. Davoren reminded attendees to “take a big step back” because the real question is how widely metastasized a patient’s cancer may be.
“The primary diagnosis is almost never a mystery,” he pointed out. “But can you be sure that this is the cancer that you think it is?” Patients’ most emergent issue, he noted, may not be the obvious first choice.
Neuro emergencies: cord compression
The first case Dr. Davoren discussed involved a 56-year-old man with advanced prostate cancer that had progressed to bone metastases and soft-tissue masses. He presented with trouble walking, an inability to move his left leg, recent onset of right-leg numbness and a possible bowel obstruction. The ED performed a chest X-ray and a lumbar spine MRI.
On exam, the patient was found to have a palpable chest-wall mass and a huge prostate, diffuse tenderness but no spinal tenderness, and diminished leg reflexes (absent on left). Labs were mostly unremarkable, with the exception of mild anemia; the most recent PSA reading, which was done outside the facility, was 52. The chest X-ray showed multiple metastases, while the lumbar MRI identified a mass at L5 compressing the nerve root.
Physicians should start morphine for bony pain, said Dr. Davoren, and be generous with dexamethasone. But what’s the right dose of dexamethasone to use?
“It doesn’t matter whether it’s 4 mg q6, 6 q4 or 4 mg q4,” he explained. “Whatever you remember is fine.” Because dexamethasone has a 30-hour biological half-life, “just give it. And steroids should always be in your back pocket for any hem/onc emergency.”
Hospitalists should also arrange consults. Neurosurgery has the right of first refusal in such a case, he noted. But given the extent of the patient’s disease, urgent radiation treatment following an oncology consult became the near-term plan.
More imaging needed
The patient improved with urgent radiation treatment but became worse a few days later. While your first thought may be that the oncologists miscalculated the radiation dose, Dr. Davoren pointed out that “the key is more imaging.”
“There isn’t any additional history or relevant labs,” he said. “What’s happened here is that the patient has multiple levels of metastases, and even though everybody was focused on the leg, he actually has a very significant cord compression at T4. “That was discovered when doctors ordered what the patient should have received at the outset: an MRI (or CT myelogram) of the whole spine.
Bicalutamide and ketoconazole were started, the dexamethasone was increased to 10 mg q6, and neurosurgeons and cardiothoracic surgeons performed an anterior corpectomy. The patient slowly recovered sensation and went on to receive palliative radiation therapy.
One takeaway from the case, said Dr. Davoren, is that “cord compression presents as pain weeks in advance of motor symptoms,” with autonomic dysfunction following motor or sensory dysfunction. “So if you see it, it’s late!” Another key point is that hospitalists should pay particular attention to the time course of decompensation. “Rapid deterioration “over days “predicts worse outcomes than deterioration over weeks,” he explained.
Neuro emergencies: brain mets
The picture changes somewhat with neurologically compromised patients who present with headache, seizure, altered mental status or focal deficits. Those are often found to be due to brain metastases.
In cases when there’s no documented history of cancer, brain metastases are most commonly from primary lung cancer in men or lung or breast cancer in women, Dr. Davoren noted. Rarely are they from sarcomas, GI malignancies or prostate cancer.
“A sarcoma, colon or prostate cancer metastatic to the brain is as rare as hen’s teeth,” he said. “If there’s a malignancy that doesn’t make sense, a biopsy will be necessary.” In his VA center, he added, the average cancer patient has 2.5 cancer types on full diagnosis.
The hospitalist’s challenge with brain-tumor/metastasis patients is to move the workup along to complete the diagnosis “with whole-brain MRI, ideally “while addressing emergent problems. Patients with brain edema and focal symptoms should be given dexamethasone, approximately 16 mg daily, which can be tapered after radiation therapy ends.
“We give patients dexamethasone if there’s edema, even if they’re asymptomatic, because they will have some degree of swelling during radiotherapy,” Dr. Davoren said. “Even if they look like a million bucks and you think there’s plenty of room for the brain to expand during radiation, there really isn’t. Those patients need dexamethasone.” Use phenytoin only if seizure activity is witnessed or strongly suspected, he advised.
“Empiric therapy with Dilantin or another anticonvulsive is not needed unless a brain met has been previously resected or debulked.” Dr. Davoren also reminded hospitalists that it’s not uncommon to see patients who survived cancers a decade or two ago showing up with a new tumor. That makes it even more important to make sure you get the long-term picture when taking a history.
Imaging results will dictate the next steps. Consult neurosurgery first if there’s no previous cancer diagnosis or the tumor is “clearly an isolated met,” he noted. Radiation oncology will consider gamma-knife or stereotactic radiosurgery for up to three isolated metastases, if neurosurgery thinks the patient isn’t a good candidate for a more invasive procedure.
Ultimately, as with cord-compressing tumors, surgery followed by radiation therapy improves survival vs. either therapy alone. But for the most part, patients with many metastases will not be surgical candidates.
The next case involved a 51-year-old man with acute-onset rib and back pain, cough, and family-reported weight loss and confusion. Lab values from the ED showed a calcium of 11, an albumin of 1.8, a white blood cell count of 6.3 and, most remarkably, a life-threateningly low hematocrit value of 16.9.
“There’s no doubt he’s got hypercalcemia, and it’s almost certainly from multiple myeloma,” Dr. Davoren said. “Why else would he be so anemic and have such crappy values?”
In his experience, he added, such patients typically are living independently or come in from a nursing home because the problem tends to progress gradually. Of the common manifestations of hypercalcemia, patients present less with the classic “stones, bones, abdominal moans and psychic groans” than complaints about constipation, anorexia and confusion.
Even without actually bony metastases, Dr. Davoren noted that such patients “certainly have a humoral hypercalcemia. What we tend to see is breast and lung cancer and myeloma with bony involvement. Prostate cancer goes to bone, all day every day, but it rarely causes hypercalcemia. “Even if a patient has widely metastatic prostate cancer and hypercalcemia, hospitalists should “still be looking for something else.”
How should hospitalists begin treating while they wait for a definitive diagnosis? For starters, these patients tend to be volume-depleted, so get normal saline on board immediately. Patients should be, as Dr. Davoren put it, “flooded until they can’t take it anymore. Then use Lasix to manage the volume.”
Consider zoledronic acid the first-line therapy for an IV bisphosphonate “but avoid it if there’s clear renal insufficiency.
“That will definitely make it worse,” said Dr. Davoren. Pamidronate is “the better drug,” even though your pharmacist may balk at the choice. In patients whose creatinine clearance is under 30, reduce pamidronate to 30 mg, use four units/kg of subcutaneous calcitonin every 12 hours and hope renal function improves. But go ahead with full-dose bisphosphonate when hypercalcemia is severe.
“It’s actually appropriate to give full-dose pamidronate if the hypercalcemia is severe, but 30 mg is also fine. You don’t have to fix the calcium with a bisphosphonate the first day,” he reminded attendees. Dr. Davoren also advised against starting with the newer osteoclast inhibitor denosumab because doctors don’t have enough experience with it yet.
You may want to make an exception, however, for patients with low creatinine clearance because one of the drug’s side effects is hypocalcemia. And, except in myeloma cases, “hypercalcemia predicts short survival,” he said.
“For a hypercalcemic patient with lung cancer, start the palliative care and hospice discussion now, even though you may be fixing the problem.”
Chronic lymphocytic leukemia (CLL) is becoming more common, and many of these patients now undergo chemotherapy almost chronically. The third case Dr. Davoren described was a 77-year-old woman who had been in chemotherapy intermittently for three years and was admitted for dehydration, fatigue, mild renal insufficiency and anemia. She undergoes transfusion, but on day two, a panicked lab calls to alert you of the patient’s neutrophil count “400/mm3 “while the nurse reports a temperature of 100.8.
This life-threatening neutropenia, Dr. Davoren stressed, is an emergent situation requiring a stat response: cefipime and vancomycin within 60 minutes (vancomycin is required only if there’s an indwelling catheter), along with repeat blood and urine cultures to look for a source, and a chest X-ray.
Also consider subcutaneous filgrastim, granulocyte colony-stimulating factor analog in a dose of 5 mcg/ kg daily when warranted; according to Dr. Davoren, it’s warranted when the neutropenia is profound or when patients are older and septic. While no major oncology organizations include colony-stimulating factors in their guidelines for patients who are already neutropenic and infected, he’s found that the therapy can turn some patients around more quickly.
Neutropenic fever is typically an effect of “day 10 to 15 of chemotherapy” and it is not caused by a malignancy. But part of the problem is that, with so much chemotherapy now delivered orally and scheduled by a nurse or pharmacist over the phone, “it’s hard to know when patients started their therapies or if they’re combining drugs,” he said. “The traditional timing is really changing.”
Even more importantly, Dr. Davoren stressed, this is a “right-now, this-minute emergency. It’s really important to recognize the time sensitivity in this.” The mortality rate for patients with febrile neutropenia, he pointed out, is 33% if antibiotics are given later than 60 minutes after presentation vs. 20% if they’re delivered in the first hour.
“Gram-negative organisms are the killers,” he pointed out, but identifying the infection source is less important than tackling it aggressively. “More than three-quarters of the time we actually don’t end up identifying an organism at all, so treat empirically for gut flora with whatever antibiotic is your favorite or your hospital likes the most.” And if the patient doesn’t respond in a couple of days, consider adding fungal coverage.
Bonnie Darves is a freelance health care writer based in Seattle.
Tackling acute thrombocytopenia
IN A SESSION on hem/onc emergencies presented during a conference on managing hospitalized patients, J. Ben Davoren, MD, PhD, an oncologist at the San Francisco VA Medical Center, raised the case of a 51-year-old woman admitted for community-acquired pneumonia who after a couple of days isn’t really getting better.
“Then you get paged from the lab that her morning platelet count is only 14,000/mm3,” Dr. Davoren said. You’ll need to order a prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen to rule out disseminated intravascular coagulation (DIC), and a lactate dehydrogenase (LDH) to rule out thrombotic thrombocytopenic purpura (TTP). You’ll also need to find out if the patient has received any form of heparin in the past week. But here’s the most important question you need answered: Is the patient bleeding?
“We can talk all day about this theory of giving platelets to somebody with ITP [idiopathic thrombocytopenic purpura], TTP or DIC,” he noted. “But if patients are profoundly thrombocytopenic and bleeding, they need platelets, regardless of etiology.”
The big three of acute thrombocytopenia, Dr. Davoren reminded the audience, are HIT, TTP and DIC. In working toward a diagnosis, doctors should remember that bleeding is more common in DIC, while clotting is more common in HIT and TTP.
“But pay attention to the companion features,” he said. “We get very excited about the fact that everybody is on heparin, but really the heparin exposure should have been between four and 10 days before this greater than 50% fall in platelet count. That’s really the basis for the diagnostic criteria.
If HIT is your leading diagnosis, a positive ELISA is not diagnostic, although “a negative one is reassuring. A serotonin-release assay is the gold standard, but unfortunately takes a long time to get back.” If you are considering HIT, administer a direct thrombin inhibitor, he added. Bivalirudin is “what we use when we can, but it has to be adjusted if there’s renal insufficiency.” The converse is true for argatroban: Adjust it for hepatic insufficiency.
If patients have confirmed HIT and their platelet count gets better in a couple days, your next step is to look for a clot. Because you have to transition these patients to warfarin, you’ll need to know how long to anticoagulate them.
“If they have no clot, anticoagulation should last three or four weeks,” Dr. Davoren pointed out. “But with a clot, patients should be anticoagulated for at least six months and perhaps indefinitely.”
A normal LDH excludes TTP. But if TTP is your leading diagnosis, a daily plasma exchange is standard therapy. “It does appear to be better, faster and more durable if 1 mg/kg prednisone is added,” he said. Clinical improvement, along with a stabilized platelet count and LDH, should be obvious within a few days.
“Continue a plasma exchange every other or every third day even after platelets are recovered as sort of a taper approach,” Dr. Davoren said. Steroids should be tapered off later.
This particular patient, however, was eventually diagnosed with DIC. Dr. Davoren outlined the following therapy, in addition to treating the underlying disorder:
- check PT, PTT, fibrinogen and D-dimer twice a day;
- give fresh frozen plasma at a rate of 10-15 ml/kg to boost the INR to more than 1.5 or 2;
- give 10U cryoprecipitate if fibrinogen is less than 150;
- give platelets to keep count above 40,000;
- give vitamin K 10 mg SQ because patients are depleting liver-dependent factors; and
- if using heparin, adjust dose to normalize PT and fibrinogen but not elevate PTT (no bolus, usually 800-1000 units/hr IV).
Under what circumstances would you use heparin? When patients have definite evidence of thromboembolism, said Dr. Davoren, or if ongoing DIC labs through factor and platelet replacement are abnormal “and if the patient is having clotting or bleeding. “If there’s a problem even though the numbers look like they’re trying to get better,” he said, “then heparin is a reasonable thing to do.”