There is still room for improvement in managing febrile neutropenia. The optimal use of G-CSF remains to be defined.
—Jean Klastersky, MD
Thirty years ago, when the first supportive care meeting as a forerunner of the Multinational Association of Supportive Care in Cancer (MASCC) Symposium was held in New York, supportive care was largely ignored, with little discussion at major cancer meetings, which focused primarily on tumor-directed therapy. More recently, patient-centered research has been recognized as a major component of cancer care. Thus, 30 years later, at the Annual MASCC Symposium, again in New York, and now the MASCC/ISOO Annual International Symposium, was an opportune time to review 30 years of progress in managing common treatment-induced and cancer-related symptoms, including febrile neutropenia, pain, psychosocial issues, and diarrhea.
The MASCC scoring index for febrile neutropenia and the use of granulocyte-colony stimulating factor (G-CSF, filgrastim [Neupogen] and pegfilgrastim [Neulasta]) for prevention have been the major advances over the past 30 years. Febrile neutropenia–related morbidity and mortality have declined dramatically over the past 3 decades, and newer chemotherapies are less toxic, but challenges remain, especially in the management of high-risk individuals.
“There is still room for improvement in managing febrile neutropenia. The optimal use of G-CSF remains to be defined,” said Jean Klastersky, MD, Institut Jules Bordet, Brussels, Belgium.1
In 1962, febrile neutropenia was often fatal, but today, related mortality is about 5% and the rate of complications ranges from 10% to 20%. Complications include hypotension, respiratory failure, admission to the intensive-care unit, and confusion.
“Five percent mortality is still too high. Many of these patients are young and treated with neoadjuvant and adjuvant therapy,” he added.
Cost is a major issue in managing febrile neutropenia. Dr. Klastersky pointed out that if a patient can be treated on an outpatient basis, the cost can be reduced by 50% compared with in-hospital treatment.
MASCC Risk Index
The MASCC risk index for febrile neutropenia, developed in 2000, is now an accepted tool. The index is based on burden of illness and weighted values for individual symptoms. A MASCC score > 20 predicts a 5% risk of complications (ie, low risk), and these patients can be treated with oral antibiotics as outpatients. He emphasized that low-risk patients with febrile neutropenia should be hospitalized and observed for 24 hours prior to discharge for outpatient therapy.
The rates of death and complications are higher in individuals with a MASCC score < 15 compared with ≥ 21, he said. Patients at high risk should be hospitalized and treated with broad-spectrum intravenous antibiotics and vigorous resuscitation if needed.
“Several studies have confirmed that a low MASCC score predicts for severe sepsis. We need clearly defined protocols. Patients with febrile neutropenia and poor MASCC score are sometimes kept too long in the emergency department (ie, several hours) without antibiotics. We should probably be much more aggressive and select patients at high risk,” Dr. Klastersky commented.
Use of G-CSF
Prophylactic use of G-CSF reduces the incidence of febrile neutropenia by about 50% and reduces mortality as well. Both long-acting and short-acting G-CSF can be used for patients with a 20% or greater risk of developing febrile neutropenia. The risk varies with different chemotherapy regimens.
“By strict definitions, patients with a calculated risk < 20% are not eligible for G-CSF. I take issue with that. When low-risk patients develop febrile neutropenia, they have rates of mortality and complications similar to those of higher-risk patients, and lower-risk patients benefit when they get G-CSF,” he stated.
Perhaps criteria should be expanded for use of G-CSF as effective primary prophylaxis to include those at lower risk, Dr. Klastersky suggested. Also, more affordable formulations of G-CSF are needed, and perhaps shorter schedules can be used to reduce associated costs.
Depression, Anxiety, and Beyond in Patients with Cancer
“For a long time, we treated the tumor rather than the person. A patient’s psychological status was not taken into account, and mental problems were not discussed. In about 1975, the stigma of silence was broken and the field of psycho-oncology was evolving with a multidisciplinary approach to measure the psychological impact of cancer on patients and the impact of personality and behavior on cancer risk and survival,” said Jimmie Holland, MD, Memorial Sloan-Kettering Cancer Center, New York, a pioneer in the field.2
Quantitative instruments are now available to measure patients’ subjective symptoms, including health-related quality of life, pain, fatigue, anxiety, depression, and delirium. “About one-third of patients with cancer exhibit significant psychosocial problems at some point in their illness,” Dr. Holland said, and the percentage is even higher with specific tumor sites such as lung, brain, and pancreas.
Use of the term “distress” has normalized the physician-patient conversation about psychological issues since words such as “psychiatric” and “psychological” are seen by many as stigmatizing. Doctors are often equally uncomfortable with such words, but all agree it is normal for the patient to be distressed—the issue is how much.
The National Comprehensive Cancer Network (NCCN) now has standards of care and practice guidelines for recognizing, monitoring, and documenting psychosocial distress. The NCCN brief screening tool known as the Distress Thermometer is based on a single question: What is your distress level this past week on a 0–10 scale? A score of 4 or above triggers a second level of questions to determine the cause and to triage patients to the proper psychosocial resources if needed.
A strong evidence base in the literature supports the benefit of psychosocial interventions for patients with cancer, as well as psychotropic medications. Based on the data, the Institute of Medicine established a new quality standard of care noting that quality care today must integrate the psychosocial into routine cancer care.
Patients should continue to be screened for psychosocial distress at regular intervals, she said.
“This is a new standard, and we are working on incorporating this into clinical care,” Dr. Holland stated. The American College of Surgeons Commission on Cancer has endorsed the new standard as part of their accreditation for centers. Over 30 international cancer organizations including the UICC, SIOP (pediatric), LiveStrong, and the International Psycho-Oncology Society have endorsed the standard on a global level.
The quality of psychosocial care delivered in oncology practices also needs to be assured. “Most cancer care is delivered in community oncology offices, but these practices have the fewest psychosocial resources,” Dr. Holland noted. ASCO is addressing this with its Quality Oncology Practice Initiative (QOPI). Thus far, 100 community practices have gotten QOPI certification, and the number is expected to grow.
“Now we have evidence-based interventions and treatment guidelines. We need to screen every patient and make this part of routine care. We needed science to bring to the table to be taken seriously. Science is important, but don’t forget the humanism,” she emphasized.
“We now have great science, great policy, and great advocacy for cancer pain. We still need better drugs and better treatments, and we need to ensure that patients are treated for their pain. We know the epidemiology, the syndromes, and the barriers. We have validated measures to assess pain and related symptoms. I would like to say we have reduced those barriers, but they continue to exist,” stated Kathleen M. Foley, MD, Palliative Care & Pain Management, Memorial Sloan-Kettering Cancer Center, New York, who was one of the earliest advocates for the importance of relieving cancer-related pain.3
“The need for alleviation of cancer-related pain is not over yet,” Dr. Foley stated. “The good news is that there is an enormous international consensus that we should treat cancer pain. We have science to support this, and now it is a matter of policy. Organizations such as the International Narcotic Control Board, World Medical Association, International Association for the Study of Pain, World Health Organization, Human Rights Council, and UICC agree that pain control is a human rights issue,” Dr. Foley told listeners. “In some countries, like the Ukraine, inadequate pain treatment is considered a form of torture.”
Advances in Pain Control
The various mechanisms of breakthrough pain, incidence pain, movement pain, and spontaneous pain have been described, and treatments exist for each of these types of pain. Opioids are the mainstay of therapy and come in different formulations, including slow-release, transdermal, transmucosal, intranasal, sublingual, and patient-controlled analgesia. New topical agents have been identified, including a eutectic mixture of local anesthetics (EMLA) cream for blood draws, and lidocaine patches (Lidoderm) for allodynia associated with neuropathic pain. Understanding of the molecular biology of pain has improved, and pharmacogenetic studies are identifying which patients can respond to specific pain medications.
Other fairly recent developments include new opioid analgesics without the side effects of traditional opioids, identification of NMDA receptors as mediators of pain tolerance and neuropathic pain, and bisphosphonates for the treatment of bone pain.
Chemotherapy-induced Nausea and Vomiting
In 2012, control of chemotherapy-induced vomiting has been largely achieved, but complete control of nausea continues to be elusive, according to Richard Gralla, MD, Medical Director, Quality of Life Research Associates, New York.4
“Patients with complete control of emesis during chemotherapy rank their quality of life the same as they did 3 days before the initiation of chemotherapy. If we don’t control emesis, patients experience more than a 30% decline in quality of life. No other side effect in the immediate period around chemotherapy has this magnitude of an effect on quality of life,” he said.
In the 1990s, the 5-HT3 antagonists graniseteron, ondansetron, and dolasetron (Anzemet) were introduced. Along with corticosteroids (such as dexamethasone), complete control rates of both acute and delayed emesis were greatly improved. Complete control of emesis then occurred in about 50% to 60% of patients by 1995.
In 2010, the combination of a 5-HT3 receptor antagonist plus corticosteroids plus a neurokinin 1 (NK1) receptor antagonist resulted in achieving complete control in 85% of cisplatin-treated patients and 75% of those receiving anthracyclines plus cyclosphosphamide.
Palonosetron (Aloxi), the most recently introduced 5-HT3 antagonist, plus dexamethasone improved control of delayed emesis when compared in a large randomized trial with granisetron plus dexamethasone in patients treated with cisplatin or anthracycline plus cyclophosphamide chemotherapy, and is now recommended by all major guideline groups in various emetic settings. Additionally, oral 5-HT3 antagonists are as effective as IV 5-HT3 antagonists, Dr. Gralla noted.
Aprepitant (Emend), the only NK1 receptor antagonist on the market, represents the newest class of antiemetics to be FDA-approved. Other NK1 antagonists, such as netupitant and rolapitant, are under study, he said.
A three-drug combination of a serotonin antagonist, dexamethasone, and aprepitant improved control of emesis even further when given with each cycle when patients were receiving anthracyclines plus cyclophosphamide. “Patients [on emetogenic chemotherapy] need protection during every cycle of chemotherapy. This three-drug regimen was better initially and increasingly superior when compared with a two-drug regimen over multiple cycles of treatment,” he stated.
Vomiting is now controlled in the large majority of patients receiving guideline-recommended antiemetics, and in nearly 100% of patients in some newer trials. “Nausea is still a miserable problem for our patients. We need quality trial designs and new agents,” Dr. Gralla said.
“MASCC has led the way in developing evidence-based antiemetic guidelines…. Our goals are to completely eliminate vomiting and nausea in every patient during every cycle of chemotherapy,” Dr. Gralla stated. ■
Disclosure: Drs. Klastersky, Holland, and Foley, reported no potential conflicts of interest. Dr. Gralla is a consultant to and receives honoraria from Merck and Helsinn.
1. Klastersky J: A 30-year perspective: Progress in febrile neutropenia in patients with cancer. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012.
2. Holland J: A 30-year perspective: Progress in approaching depression and anxiety in patients with cancer. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012.
3. Foley K: A 30-year perspective: Alleviation of pain: From research to practice. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012.
4. Gralla R: A 30-year perspective: Progress in antiemetic therapy in patients with cancer. MASCC/ISOO International Symposium on Supportive Care in Cancer. Presented June 28, 2012.