Chemotherapy-Induced Peripheral Neuropathy and its Impact on Health-Related Quality of Life among Multiple Myeloma Patients: A Single-Center Experience.

I NTRODUCTION

Advances in cancer therapy have led to a gradual shift in long-term treatment effects, patient-reported outcomes, and patient experience.[ 1 ] Chemotherapy-induced peripheral neuropathy (CIPN) is a common long-term neurologic side effect after chemotherapy,[ 2 ] with debilitating symptoms that negatively impact on a patient's quality of life (QoL).[ 3 ] The incidence of CIPN ranges between 30% and 70%,[ 4 5 ] with the wide variation likely due to the use of different methods to assess CIPN assessment. CIPN incidence rate depends on the type and dose of the chemotherapy,[ 6 7 ] and the prevalence decreases with time since starting chemotherapy: 68% of patients experience it in the 1 st month, 60% at 3 months, and 30% at 6 months.[ 8 ]

Multiple myeloma (MM) is cancer of clonal plasma cells, and it makes up 10% of all hematological malignancies.[ 9 10 ] Usual therapeutic management includes immunomodulatory drugs (thalidomide) and proteasome inhibitor (bortezomib).[ 10 ] CIPN more commonly occurs in patients receiving platinum-derived compounds (cisplatin, carboplatin, and oxaliplatin), taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine and vinblastine), and proteasome inhibitors (bortezomib).[ 11 12 13 14 ] The first-line treatment for patients diagnosed with MM, bortezomib, causes CIPN in 75% of patients.[ 12 15 ]

The development of CIPN symptoms depends on the used chemotherapy. The symptoms affect upper and lower limbs, in a “stocking-and-glove” pattern, and the orofacial region.[ 6 16 17 18 ] Onset of symptoms is gradual, starting in the lower limbs and migrating to the upper limbs.[ 2 ] Sensory symptoms such as pain, dysesthesia, numbness, and tingling in the hands and feet are more prevalent and predominant than autonomic symptoms (constipation, urinary retention, and erectile dysfunction).[ 6 13 16 19 ] Clinical examination reveals impairment of perception of touch vibration and proprioception.[ 1 ] The symptoms can be debilitating and impair QoL.[ 2 20 ] Several tools have been reported in literature to assess CIPN.[ 7 13 21 22 23 24 25 ] The European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire for CIPN 20-item scale (QLQ-CIPN20) is reported to have good reliability and internal validity (Cronbach's α: 0.88).[ 24 26 27 ]

CIPN needs to be recognized as a serious health issue among patients diagnosed with MM. The study aims to assess self-reported CIPN symptoms and the effect of these on health-related QoL (HRQOL) in patients diagnosed with MM.

M ETHODS

A cross-sectional survey to assess CIPN and HRQOL in patients diagnosed with MM was conducted in August 2016 in a tertiary care hospital. Ethical approval was obtained from the Institutional Review Board (IRB) with the approval number (RSS16/005).

Study participants

A convenient sample of patients aged 18 years and above, male/female, diagnosed with MM since 2010, started on chemotherapeutic agents and attending the hematology clinics/ward at a tertiary care hospital were invited to participate in the study. Patients were enrolled after signing written informed consent.

Instruments

CIPN was assessed using the Arabic version of self-reported tool, EORTC QLQ-CIPN20, composed of 20 items: three subscales examining sensory (nine items), motor (eight items), and autonomic symptoms (three items). Items were rated on a Likert scale: 1, not at all; 2, a little; 3, quite a bit; and 4, very much. Final scores were linearly transformed from 0 to 100, with a higher score denoting increased symptom burden.[ 24 ] HRQOL was assessed using the Arabic version of EORTC Multiple Myeloma Module, QLQ-MY20. It consists of two subscales: a functional domain (4 items) and a symptoms domain (16 items). Scores were linearly transformed to a 0–100 scale, with a higher score denoting a better QoL.

The Arabic validated versions of EORTC QLQ-CIPN20 and EORTC multiple myeloma module (QLQ-MY20) were distributed to the participants during their follow-up visit in the hematology clinics or ward. The participants could read and write Arabic. On an average, participants took 5 min to complete the questionnaire. The self-completed questionnaire was collected in an envelope to maintain the confidentiality of the responses. Participants' demographic data and clinical information were collected from electronic health records.

Statistical analysis

Categorical variables, i.e., gender, comorbidities, MM type, disease stage, chemotherapy received, history of chemotherapy/radiotherapy, family history of MM, and treatment outcomes, were reported in frequency tables and percentages. Age and duration of MM diagnosis were reported as mean and standard deviation. Results from the QLQ-CIPN20 and QLQ-MY20 were presented using descriptive statistics. The QLQ-CIPN20 results were compared across subscales for diabetic and nondiabetic patients using the Wilcoxon rank-sum test. Significance was taken as α < 0.05. Analyses were carried out using SAS version 9.4 (SAS Institute, Cary, NC, USA).

R ESULTS

Patients characteristics

Sixty-two patients filled in the questionnaire, 37 men (60%) and 25 women (40%), with a mean age of 58.74 ± 11.49 years [ Table 1 ]. The mean duration of MM was 3.08 ± 2.68 years. Almost two-thirds of patients (49/62, 79%) received active chemotherapy, with bortezomib-cyclophosphamide -dexamethasone including bortezomib as the most common regimen 31 (63%) ( n = 49). In total, 12 (25%) patients received thalidomide. Some patients have received more than one neurotoxic agent 6 (12%). Twelve (22%) patients had received radiotherapy. Half of the patients received autologous stem cell transplantation (31 patients). In terms of comorbidities, 18 (34%) were known to have diabetes mellitus, 18 (34%) were known to have hypertension, and 3 (6%) had ischemic heart disease. Overall, 5 (9.0%) patients had prior malignancy and 5 (10%) had myelodysplastic syndrome. Information on response to treatment data was available for only 23 patients: 9 (39%) patients had relapse, 8 (35%) had partial response, and 6 (26%) had complete response [ Table 1 ].

Chemotherapy-induced peripheral neuropathy symptoms among multiple myeloma patients

The CIPN symptoms are summarized below for participants who had reported (“quite a bit”/”very much”).

On the sensory scale, of the 62 participants, 20% had reported tingling in fingers/hands and 23% in toes/feet. Numbness was reported by 39% in fingers/hands and 37% in toes/feet. Shooting or burning pain was reported by 14% in fingers/hands and 26% in toes/feet [ Figure 1 ]. Trouble standing or walking was reported by 43%. Hearing difficulties were reported by 17%, whereas only 3% had reported difficulty distinguishing between hot and cold water.

On the motor scale, the most commonly reported symptoms were trouble walking 40% and difficulty in climbing stairs and standing up from a chair 60%. The driving question was analyzed for the 25 participants who drove: 44% reported “quite a bit” or “very much” for the question about trouble using pedals when driving.

On the autonomic scale, participants who reported “quite a bit” or “very much” were summarized as follows: 27% reported symptoms of orthostatic hypotension, 31% had blurred vision, and 46% reported erectile dysfunction [ Table 2 ].

Comparing mean scores on the CIPN subscales between patients with/without diabetes did not show statistically significant differences for the sensory ( P = 0.162), motor ( P = 0.866), or autonomic ( P = 0.474) scales [ Figure 2 ].

Quality of life among multiple myeloma patients

The proportions of the 62 participants who reported “quite a bit” or “very much” on QoL scales are as follows.

Half of the participants reported aches and pain. Back pain was reported by 42%, with an increase in pain on activity reported by 49%. More than half (57%) reported that they had felt ill, 43% reported having a dry mouth, and 33% reported losing hair. Half of the respondents reported having tingling hands or feet. Just over one-third (35%) reported that they had been thinking about their illness, and 28% were worried about their health in the future [ Table 3 ].

Chemotherapy-induced peripheral neuropathy between chemotherapy with and without bortezomib

The CIPN symptoms were compared across patients who had received chemotherapy with and without bortezomib. The symptoms are not statistically different between two groups, except blurry vision which is significant ( P = 0.03) [ Supplemental Table 1 ].

D ISCUSSION

Peripheral neuropathy is the most common side effect of chemotherapy among MM patients. However, the neuropathy symptoms are not necessarily related to chemotherapy, and it can be age related and with other comorbid conditions such as diabetes. This study shows that EORTC QLQ-CIPN20 is a valid instrument in identifying CIPN in MM patients. Participants took, on average, 5 min to complete the Arabic questionnaire, making the use of the tool feasible in the routine care of MM patients.

CIPN associated with the use of bortezomib and thalidomide is reversible.[ 28 29 ] When bortezomib is discontinued, 80% of patients become asymptomatic.[ 28 ] However, symptoms can continue after discontinuation of chemotherapy,[ 1 ] and cure is not guaranteed once chemotherapy stops.[ 2 ] Capturing CIPN symptoms and change overtime is crucial for chemotherapy dose monitoring.

A comparison of these results with those of other studies is challenging. The QLQ-CIPN20 is not commonly used for myeloma patients, except few studies.[ 27 30 ] The sensory symptoms reported by participants in this study occur less frequently than in the study reported by Wolf et al .:[ 27 ] tingling in fingers/hands (20% vs. 63%), numbness in fingers/hands (39% vs. 57%), and shooting/burning pain in fingers/hands (14% vs. 18%).[ 27 ] The symptom frequencies are also lower than those reported by Beijers et al .:[ 30 ] tingling (37%), shooting/burning pain (37%), and numbness (27%) in upper and/or lower extremities. However, erectile dysfunction was reported more commonly in the current study participants (46% vs. 28%).[ 30 ]

CIPN can be difficult to differentiate from other forms of peripheral neuropathies, for example, diabetic and paraneoplastic neuropathies.[ 1 31 ] In the current study sample, 86.9% of participants reported at least one symptom that bothered them “quite a bit” or “very much” and impacted their daily life activity, which is higher than that reported in an earlier study (53%).[ 30 ]

Patients with MM experience low HRQOL. Several tools have been reported to capture HRQOL among MM patients; however, the EORTC QLQ-MY20 is a disease-specific instrument.[ 32 ] Floortje et al . reported worse QoL scores among MM patients compared with healthy individuals using the EORTC QLQ-C30; the scores in the MM respondents deteriorated over time. The symptoms reported in this patient group were less frequent than in the current study sample for nearly all measures: tingling hands/feet (32% vs. 50%), back pain (28% vs. 42%), bone aches/pain (26% vs. 50%), worried about future health (34% vs. 28%), and worried about dying (21% vs. 20%).[ 33 ] However, the duration of MM diagnosis was 10 years compared with the 5-year duration in the current study participants.[ 33 ]

The hearing difficulty based on EORTC QLQ-CIPN20 was high 17% in our study compared to earlier studies (5%) with different cancer diagnosis[ 34 ] and 11% among colorectal cancer patients.[ 33 ] A case report had reported bilateral hearing loss with four doses of bortezomib among a MM patient.[ 35 ] Whether the hearing difficulty is due to bortezomib, age related or due to complication of myeloma itself is beyond the scope of this study.

Limitations

The baseline disease status of participants could not be captured; therefore, an overlap with preexisting peripheral neuropathy symptoms due to diabetes could not be excluded. As there was no control group, it would be difficult to assess whether the observed frequencies differ from those in the wider population. Although we have captured all the patients diagnosed with MM over the 5 years, the sample size is not reasonable enough to draw the conclusion that peripheral neuropathy is caused by a specific chemotherapy.

C ONCLUSION

The self-reported EORTC QLQ-CIPN20 is a reasonable tool to capture CIPN among MM patients. CIPN is associated with impaired HRQOL. Chemotherapy dose modification or discontinuation according to symptom severity is needed. Capturing CIPN as a patient-reported outcome needs to be considered in routine clinical practice.

Ethical approval

This is an observational study. The study was approved by King Abdullah International Medical Research Center, Institutional Review Board (IRB), with approval number (RSS16/005).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgment

The authors thank all the participants who had participated in the study and the nurses at the Department of Hematology for their support.

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