In this issue of Blood, Geyer et al1 report results from a large multinational survey in which a sizeable proportion of patients with myeloproliferative neoplasms experienced severe symptom burden. However, standard measures of disease severity and risk did not always predict which patients would have high levels of symptom distress.
Model of symptom burden (symptom status plus functional status) as a subset of health-related quality of life (HRQOL). HRQOL is an inclusive concept with many domains outside of those that are most likely to be affected by disease and treatment. In contrast, symptoms (black circle) are patients’ perceptions of what is closest to the disease and treatment process. The biology of symptom burden (gray oval) provides the rationale for the development of effective management strategies. Adapted figure used with permission from Charles S. Cleeland6 based on the concept from Wilson and Cleary.7
Model of symptom burden (symptom status plus functional status) as a subset of health-related quality of life (HRQOL). HRQOL is an inclusive concept with many domains outside of those that are most likely to be affected by disease and treatment. In contrast, symptoms (black circle) are patients’ perceptions of what is closest to the disease and treatment process. The biology of symptom burden (gray oval) provides the rationale for the development of effective management strategies. Adapted figure used with permission from Charles S. Cleeland6 based on the concept from Wilson and Cleary.7
The availability of new agents to treat hematologic malignancies, including many with molecular and genetic targets, is producing better disease control and significantly extending survival.2 As a result, various hematologic cancers that before were rapidly fatal have become chronic conditions that can be managed with continued treatment.3 When treatment only marginally extended survival, life-threatening toxicities were the main concern in making decisions about the acceptability of therapy; today, with significantly prolonged survival, it is critical that we expand our view of the outcomes of therapy to include how patients feel and function during extended periods of treatment. Given that an increasing number of therapies have similar survival outcomes, documenting better functioning, reducing disease-related symptoms, and causing fewer treatment-related symptoms create a significant therapeutic advantage. Knowledge about the effects of a particular agent on symptomatic and functional status is helpful for both patients and their health care teams as they choose among treatments with similar standard clinical outcomes.
There has been a long tradition of evaluating treatments for metastatic solid tumors in terms of relative impact on health-related quality of life (HRQOL). For hematologic malignancies, however, less attention has been paid to eliciting the patient’s experience during treatment—perhaps because of the lethality of many of these cancers. One reason for the reluctance to include HRQOL measures in hematologic malignancy clinical trials is the additional costs and time commitments required of investigators and patients to administer and complete patient-reported questionnaires (measuring these toxicities via clinician ratings, a typical approach, does not optimally capture the patient experience during therapy). Also, many HRQOL questionnaire items address the patient’s perception of life domains that are less pertinent to the direct effects of the treatment and disease and therefore insensitive to changes during treatment. The most sensitive measures of response to therapy are usually the patient’s report of changes in symptoms as treatment progresses.4 These disease-related and treatment-specific symptoms are often referred to as symptom burden,5 as Geyer et al1 note.
Symptoms and their impact on functioning are conceptually most proximal to the disease process and its alteration by treatment (see figure6,7 ). If the symptoms most relevant to the disease and treatment being studied can be identified, patient ratings can be gathered in a few minutes via a short, targeted questionnaire, thus significantly reducing patient and investigator time and cost. These short questionnaires are highly compatible with electronic data capture, allowing more frequent assessment of symptoms from patients away from the clinic via computer-assisted telephone assessments, Web applications, and smart phones. Frequent data collection during a trial can answer questions about when patients can expect treatment-related symptom burden and disease-related symptom relief.
Identification of the symptoms most appropriate for evaluation of a particular agent in a particular malignancy is a complex process, and complete consensus about how this should be done is lacking. One approach is that used to develop the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).8 MPN-SAF symptom items were selected from those most endorsed by an international sample of patients with myeloproliferative neoplasms. The final MPN-SAF used by Geyer et al1 includes 10 symptoms most representative of myeloproliferative neoplasms, scored on a 0 (absent) to 10 (worst imaginable) scale. In a recent clinical trial of ruxolitinib, a Janus kinase inhibitor, in patients with myelofibrosis, the MPN-SAF documented substantial rapid improvement in several symptoms, including fatigue, weight loss, night sweats, and pruritus, and in daily functioning.9 This proof of clinical benefit led to inclusion of symptom reduction in the Food and Drug Administration labeling indications for ruxolitinib for the treatment of myelofibrosis, evidencing the important contribution that symptom assessment can have in hematologic malignancy clinical trials.10
Within the drug development and evaluation process, the systematic administration of symptom measures at frequent intervals in early-phase clinical trials can supply critical information about treatment toxicities or symptomatic benefits, such as reduction of disease-related symptoms and improved function. Qualitative interviews with patients can verify that salient symptoms are being assessed and capture additional treatment-related symptoms that should be added to routine assessment. Even though these trials may enroll fewer than 100 patients, early evidence of multiple treatment-related toxicities can serve as a warning that adherence to treatment may be compromised and that the appropriateness of dose selection or plans for supportive care may need to be reconsidered.11
The Eastern Cooperative Oncology Group conducted the nationwide Symptom Outcomes and Practice Patterns (SOAPP) study (www.ecogsoapp.org) to create a database that includes symptoms reported by >3000 patients with breast, lung, prostate, or colorectal cancer using the MD Anderson Symptom Inventory, a brief, concise multisymptom assessment questionnaire.12 With the work of Geyer et al,1 such a database now exists for myelofibrosis patients. A similar database for hematologic malignancies would be highly valuable. Baseline data on symptoms for standard treatments can be extremely useful in planning and evaluating clinical trial outcomes for new therapies. Applying various methods of symptom clustering, one of which was used by Geyer et al,1 may help in developing hypotheses about the pathophysiology of symptoms. These data will also identify areas of need for symptom management to improve functioning and increase treatment tolerability for patients with hematologic malignancies.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
