Aim

To summarize the validity of the following outcome measures:

• skeletal-related events
• spinal cord compression
• pathological fractures
• Analgesic Quantification Algorithm (AQA)
• Brief Pain Inventory (Short Form) (BPI-SF)
• Functional Assessment of Cancer Therapy–General (FACT-G)
• EuroQol 5-Dimensions Questionnaire (EQ-5D).

Findings

Table 21 provides a detailed summary of the findings.

Table 21

Validity of Outcomes.

Skeletal-Related Events

This primary outcome was defined as the occurrence of one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Generally, these events are considered hard outcomes and objective in nature. Our clinical expert, however, informed us that pathological fractures in patients with bone metastases do not necessarily require intervention, and the effect of these fractures on pain levels and quality of life varies in nature. The clinical expert expressed that only fractures that required an intervention are clinically important.

Spinal Cord Compression

Spinal cord compressions are the result of an abnormal mass exerting pressure on the spinal cord. This can be due to a number of reasons, including a fractured vertebra, herniated disk, or tumour metastases. Spinal cord compression can cause clinical manifestations of varying degrees of intensity, ranging from numbness and weakness to loss of limb function. The definitive diagnosis of spinal cord compression is based on radiologic findings. This outcome can be considered objective, although the extent of the clinical importance of milder cases of spinal compression is not clear.

Pathological Fractures

Pathological fractures are bone fractures that happen in the absence of serious trauma. In patients with metastatic cancer, this can manifest clinically as sudden pain, and can cause varying degrees of loss of function and deterioration in the quality of life. In other cases, pathological fractures can be asymptomatic and discovered incidentally in radiographic diagnostics for other indications. The definitive diagnosis of this outcome occurs through radiographic findings, with a high degree of objectiveness in these findings. Due to the variability in the severity of presentation, the clinical expert consulted on this review was of the opinion that only fractures that require an active intervention with surgery or radiotherapy are clinically significant.

Analgesic Quantification Algorithm

AQA is an analgesic score that captures the daily intensity of the analgesic used in pain management. It consists of a minimum score of 0 (no analgesic) and up to 7 (strong opioid > 600 mg oral morphine equivalent [OME] per day) as shown in Table 22.

Table 22

Analgesic Score.

Chung et al.³⁶ have shown that the AQA is a sensitive measure to capture analgesic use by comparing AQA with an older established tool (World Health Organization [WHO] analgesic treatment ladder) using the history of analgesics use in patients enrolled in a randomized controlled trial (RCT) comparing denosumab with zoledronic acid in patients with non-breast or prostate cancer metastatic tumour.⁴ No other validation parameters or minimal clinically important difference (MCID) were found for AQA.

Brief Pain Inventory (Short Form)

Designed specifically to capture pain in cancer patients, the BPI-SF mainly assesses pain intensity and pain interference with a patient’s life. It mainly consists of eight questions, with the patients indicating the severity and effects of pain on a scale from 0 (No pain/ no interference) to 10 (Worst ever pain/ complete interference).

The BPI-SF tool has been validated and shown to be reliable in many studies.^{14, 34, 37} In addition, a recent study established the MCID at 1.5 to 2.0.¹⁵

Functional Assessment of Cancer Therapy–General

The FACT-G questionnaire is a health-related quality of life instrument for patients with cancer. FACT-G consists of 27 questions evaluating four aspects of a patient’s quality of life, namely: physical well-being, functional well-being, social/family well-being, and emotional well-being.

In 1993, Cella et al. developed the FACT-G tool and assessed its reliability and validity with 854 cancer patients and 15 oncology specialists. FACT-G was found to be valid, reliable, and sensitive to change.¹⁶ FACT-G has since been used in many RCTs for cancer therapy.³⁸ The MCID for the FACT-G ranges from 3 to 7.³⁹

EuroQoL 5-Dimensions Questionnaire

The EQ-5D is a non–disease specific health-related quality of life instrument that is commonly used to estimate health utility. With a total of six questions, the first five cover mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The last question is a visual analogue scale where patients mark their health state on a 20 cm strip scored from 0 to a 100, where 0 is the worst possible health state and 100 is the best possible health state.

A structured review by Lin et al. attempted to synthesize the validity, reliability, and utility of EQ-5D from the literature. The review included 12 studies that assessed EQ-5D in cancer patients. The reviewers were in support of using the EQ-5D tool in cancer patients.⁴⁰ In addition, an MCID has been established for EQ-5D at 0.06.^{18, 19}

Conclusion

Skeletal-related events, spinal cord compression, and bone fracture are objective outcomes with possible clinical symptoms and signs and a definitive diagnosis with radiographic signs. BPI-SF, FACT-G, and EQ-5D are commonly used patient-reported outcome measures that have been validated in cancer patients and for which an MCID has been established. For AQA, although validated in cancer patients, an MCID is not known.