Disclosures: The authors would like to state that there are no conflicts of interest regarding this work.
Address correspondence and reprint requests to: Dorit Pud, PhD, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 31905, Israel. E-mail: email@example.com.
Abstract The majority of patients with breast cancer receiving chemotherapy report multiple symptoms. Compelling evidence has shown that subgroups of patients can be clustered by the severity of symptoms. Recent studies demonstrate that chemotherapy with such substances as paclitaxel can cause neuropathic pain (CINP) and consequently neural damage.
Objectives: the present study examined the relationship between symptom clusters and CINP among 40 patients with breast cancer. The study was based on 2 sessions conducted before and during paclitaxel treatment. In each session, neuropathic pain was assessed by the DN4 Questionnaire. In the second session, the Lee Fatigue Scale, the General Sleep Disturbance Scale, and the Center for Epidemiological Studies–Depression Scale were also administered, and the worst pain intensity was assessed. Using cluster analysis, 2 symptom clusters were identified on the basis of the severity of the 4 symptoms scores. Patients in the High Cluster (37%) experienced a high level of all symptoms, whereas patients in the Low Cluster (63%) experienced a low level of all symptoms. Twenty patients (50%) were diagnosed with CINP. A subgroup of patients (23%) from the High Cluster was identified as having CINP; 35% were in the Low Cluster and free of CINP. In conclusion, there appears to be a specific subgroup of patients with hypersensitive cancer who need greater attention to symptom management. Early detection of symptoms, together with careful dose selection and assessment of early stages in the development of neuropathic pain, are essential for preventing the simultaneous occurrence of severe multiple symptoms and CINP.
Several lines of evidence have shown that 25% to 50% of patients treated with chemotherapeutic agents, mainly from the taxane, vinca alkaloid and platinum classes, develop peripheral neuropathy that may be accompanied with neuropathic pain (NP) syndrome.1–3 This adverse effect is usually manifested as sensory dysfunction and severe pain.4–7 Notably, once chemotherapy-induced neuropathic pain (CINP) is evoked, it becomes the major rationale for reducing the drug regimen or even ending the treatment of choice for a specific cancer type. Consequently, it is believed that early detection and monitoring of symptoms may prevent CINP and comorbidity, while promoting better patient compliance.8–10 The fact that some patients with the same cancer type and similar chemotherapeutic regimen develop CINP while others do not warrants further investigation into individual differences in the development of CINP. Determining the factors that can predict individual response patterns to a given chemotherapy treatment will facilitate the identification of patients at high risk of developing CINP.
Besides CINP, oncology patients often experience multiple debilitating and unrelieved symptoms as a result of the cancer treatment. Over the last decade, numerous studies using the statistical method of cluster analysis have been successful in subgrouping patients with cancer into clusters based on the severity of their multiple symptoms (eg, pain, sleep disturbance, fatigue, and depression). A symptom cluster is composed of 2 or more symptoms that are related to each other and that occur together. By creating these clusters, additional significant differences between the subgroups, such as quality of life and level of functioning, have been demonstrated.11–14 The relationships between symptoms within a cluster are found to be stronger than those between symptoms across different clusters.15
The aims of the present study were to (1) diagnose CINP among a group of patients with breast cancer treated with paclitaxel; (2) determine whether subgroups of this population can be identified based on their ratings of the severity of pain, sleep disturbance, fatigue, and depression; and (3) examine the relationship between the clusters and CINP. To the best of our knowledge, this study is the first to attempt to link the symptoms experienced by breast cancer patients with the development of CINP. This approach has the potential to identify high-risk patients requiring different symptom and disease management interventions. The choice of adjuvant chemotherapy is dependent on both tumor- and patient-related factors. There is no way currently to predict the development of CINP over a small number of courses of chemotherapy. The identification of a subgroup of patients who experience a severe level of symptoms and are likely to develop CINP will help healthcare providers to tailor individual-based treatment.
The study population consisted of 40 patients with breast cancer who were treated with paclitaxel. All patients were referred to the day-care unit at Sheba Medical Center in Tel Aviv, Israel, while receiving chemotherapy. Inclusion criteria were as follows: (1) age of 18 or older; (2) no distant metastasis; (3) ability to communicate and understand the purpose and instructions of the study; and (4) provision of written informed consent. The study was approved by the ethics committee at the study site.
The study instruments included the following:
1 A demographic questionnaire provided information on age, gender, marital status, and educational background. In addition, the patients’ medical records were reviewed for additional diseases and treatment information, including disease stage and current cancer treatment.
2 The Douleur Neuropathique 4 Questionnaire (DN4) was used to identify patients with NP. The DN4 Questionnaire consists of 7 pain descriptor items, to which the subject is requested to respond in yes (1) or no (0) terms. In addition, the DN4 includes 3 questions based on a standardized clinical examination (ie, hypoesthesia to touch, hypoesthesia to a pinprick, and allodynia to a paintbrush). In this study, each examination was performed 2 times on each of the 4 extremities (the dorsal part of the palms and foot). Stimulation proceeded from the periphery toward the center of the extremities. All stimuli were performed by the same examiner. Item scores are added together to obtain a maximum score of 10, with a diagnosis of NP at the breakpoint of 4. The DN4 has well-established validity and reliability.16,17
3 The Lee Fatigue Scale (LFS) consists of 18 items that assess the level of fatigue and energy using a 0 to 10 numerical rating scale (NRS) format. A fatigue severity score is calculated as the mean of the 13 items in the fatigue subscale. The total range is from 0 to 10, with higher scores indicating higher levels of fatigue severity. The LFS has been used to measure fatigue in healthy individuals as well as in patients with cancer and a positive HIV diagnosis. The LFS has established validity and internal consistency reliability coefficients.18
4 The General Sleep Disturbance Scale (GSDS) consists of 21 items that evaluate various aspects of sleep disturbance (ie, quality and quantity of sleep, sleep onset latency, number of awakenings, excessive daytime sleepiness, and medication use). Each item is rated on an NRS ranging from 0 (never) to 7 (every day). Item scores are added together to yield a total score that can range from 0 (no disturbance) to 147 (extreme disturbance). The GSDS has well-established validity and reliability in shift workers, pregnant women, and patients with cancer or a positive HIV diagnosis.19
5 The Center for Epidemiological Studies–Depression Scale (CES-D) consists of 20 items selected to represent the major symptoms in the clinical syndrome of depression. Patients are asked to rate a series of statements indicating how frequently the symptoms were experienced in the past week. Each item is rated on a scale ranging from 0 (rarely or none of the time) to 3 (most or all of the time). Scores can range from 0 to 60, with scores greater than 16 indicating the need for patients to seek a clinical evaluation for major depression. The CES–D has well-established concurrent and construct validity.20
6 A descriptive NRS for worst pain intensity was evaluated using a descriptive NRS that ranged from 0 to 10.
After meeting the inclusion criteria, all patients signed a written informed consent. The study was based on 2 sessions. The first session took part prior to administration of the first course of paclitaxel and included the collection of demographic data as well as an assessment of NP by DN4 to detect previous NP states. This evaluation was performed on all 4 limbs (palms and feet). The second session was conducted after receiving at least 2 courses of paclitaxel to observe the development of the symptoms under study. Patients completed the LFS, GSDS, CES–D, and worst pain intensity questionnaires, along with a second evaluation by DN4. Each session lasted approximately 1 hour.
All statistical analyses were conducted using the SPSS for Windows Version 17 statistical package (SPSS, Inc., Chicago, IL, USA). Descriptive statistics and frequency distributions were generated on the sample characteristics. NP was determined by a score of ≥ 4 on the DN4. The highest score obtained from all 4 extremities was chosen for the statistical analyses for each patient. Cluster analyses were performed to identify subgroups of patients based on the severity of their symptoms (pain, sleep disturbance, fatigue, and depression). Scores from each of the measures were standardized for their ranges to “equalize” the scales of all parameters into 0 to 10 scores. Cluster analyses yielding 2 clusters were obtained from the data.
A total of 42 female patients were recruited for the study. All patients completed the study questionnaires during the first session after signing the informed consent. However, 2 patients were lost upon follow-up for the second session. Thus, a total of 40 patients had completed data on all of the study measures required and were entered into the statistical analyses.
The mean ± SD age of the sample was 45 ± 9.3 years, with a range between 21 and 65 years. Twenty-five patients (62.5%) were college graduates, and 35 (87.5%) were married or partnered. Table 1 summarizes the disease and treatment characteristics for the total sample. As can be seen, all patients were treated with 4 courses of adriamycin and cyclophosphamide (AC) followed by either 4 or 8 courses of paclitaxel. The mean ± SD scores of the 4 examined symptoms were as follows: pain 5.3 ± 3.9; sleep disturbance 43.3 ± 24.1; fatigue 4.0 ± 2.5; and depression 16.7 ± 10.9.
Table 1. Disease and Treatment Characteristics for the Total Sample (n = 40)
AC, adriamycin and cyclophosphamide.
Type 2 diabetes
4 courses AC + 4 courses Paclitaxel
4 courses AC + 12 courses Paclitaxel
Conducting cluster analysis revealed 2 clusters (ie, subgroups) based on the severity of the 4 tested symptoms. The Low Cluster group included 25 patients (62.5%) of the study sample who reported low levels of all 4 symptoms. The High Cluster group included 15 patients (37.5%) who reported high levels of all 4 symptoms. The standardized scores of all symptoms for the 2 groups are shown in Figure 1. Consequently, the patient sample was then categorized into 4 different subgroups for each cluster and the presence or absence of CINP. Figure 2 demonstrates the distribution of the patients within these 4 subgroups.
According to the DN4, 20 patients (50%) were diagnosed with CINP (with DN4 scores higher than 4), and 20 patients were categorized as non-CINP (with DN4 scores lower than 4). Table 2 illustrates the neuropathic characteristics of each subgroup. As can be seen, the CINP subgroup reported higher frequencies of neuropathic characteristics than the non-CINP subgroup in all DN4 parameters. As such, burning, painful cold, electric shocks, tingling, and pins and needles were reported by 30% to 70% of the CINP subgroup, but not stated by the non-CINP subgroup. Numbness and itching were described by 50% and 45%, respectively, by the CINP subgroup, in comparison with 15% and 20%, respectively, by the non-CINP subgroup. Interestingly, hypoesthesia, hypoalgesia, and allodynia were found in both subgroups.
Table 2. Characteristics of DN4 by Patient Subgroups (n = 40)
The main findings of this descriptive study were that (1) 2 distinct groups of patients with breast cancer, namely Low Cluster and High Cluster, were identified on the basis of their experiences with 4 highly prevalent symptoms; (2) 50% of the patients treated with paclitaxel developed CINP; (3) a combination of CINP and clusters revealed a subgroup with no evidence of CINP within the Low Cluster group (35%) and a subgroup with CINP within the High Cluster group (22.5%). These 2 subgroups may be viewed as “double lucky” and “double unlucky,” respectively.
Paclitaxel is one of the chemotherapeutic treatments of breast cancer that is associated with a high frequency of peripheral neuropathy in a dose- and exposure-dependent manner. It is characterized first by paresthesias, followed by dysesthesias.10,21 Recently, Reyes-Gibby et al.22 showed that patients with breast cancer who experienced chemotherapy-induced neuropathy (CIN) during paclitaxel treatment were 3 times more likely to develop NP.
The reason that CIN is painful for some patients and not for others is still an open question. One possible explanation may be the severity of the neuropathy, assuming that more severe neuropathy, as determined by sensory function, will be associated with more intense spontaneous activity in pain fibers. However, the few studies exploring this issue have yielded contradictory results, with some reporting no differences in sensory thresholds between the patients with painful and nonpainful CIN23–26, while others found higher sensory thresholds among the patients with painful CIN.27–30
Another possible explanation for this variation relates to the interpersonal variability in patterns of pain modulation. Binder et al.29 did not find any difference between patients with painful and nonpainful neuropathy in the extent of pain excitation, as expressed by increased temporal summation. On the other hand, Nahman-Averbuch et al.30 found that patients with CINP showed a significant impairment in their patterns of pain modulation, with enhanced excitation leading to higher temporal summation and reduced inhibition, resulting in less-efficient, conditioned pain modulation. Given these findings, the authors concluded that painfulness of neuropathy can be associated with a “pronociceptive” modulation pattern, which may be primary to the development of pain.
In line with these previous reports, we also found that only half of the patients treated with paclitaxel developed CINP. However, our findings do not indicate whether CINP is associated with pain perception and/or modulation patterns. Nevertheless, we did attempt to explore whether CINP is associated with the presentation of other symptoms. Clinical experience suggests that oncology patients often report the co-occurrence of multiple symptoms, which creates a vicious cycle of ongoing and unrelieved symptoms. Based on these clinical observations, several investigators have conducted research on symptom clusters in oncology patients.12,14,31–34
These studies prompted Miaskowski et al.35 to hypothesize that the co-occurrence of multiple symptoms (ie, symptom clusters) may produce synergistic effects, with a deleterious impact on patient outcomes and may require different treatments from those called for to treat the single symptoms within a cluster. Several previous studies have consistently identified subgroups of oncology outpatients based on their experience with a specific symptom cluster (ie, pain, fatigue, depression, and sleep disturbance).12,14,32–38
Moreover, if not complex enough, interpersonal variability in symptom experience has been established as well.39 There is tremendous individual variability in perceptions produced by an identical “generator.” Symptoms are uniquely experienced by each person, as determined by dynamic interactions among biological, socio-cultural, and psychological domains. Cleeland et al.40 suggested that the symptoms of cancer and cancer treatment may be attributed in part to cytokine-induced sickness behavior.41 The physiological responses that characterize sickness behavior in animals injected with pathophysiological components of bacteria (eg, lipopolysaccharide) include fever, pain, wasting, and increased activity in both the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system.42 In addition, the animals exhibit a variety of behaviors including cognitive impairment, a decrease in social and sexual activity and reduced food intake. This sickness behavior in animals is believed to be mediated through the release of pro-inflammatory cytokines.43,44 These physiological and behavioral responses observed in animals are remarkably similar to the phenotypic characteristics associated with symptom clusters, thus providing the basis for the claim that certain subgroups of patients may have different symptom experiences based in part on their genetic profile.
In agreement with those findings, the present study identified 2 groups of patients, 1 with Low (63%) and 1 with High (37%) symptom clusters, based on their experiences with symptoms. In addition, we showed that once a patient was identified within the High Cluster group, she was more likely to develop CINP. Conversely, if the patient was identified within the Low Cluster group, she was less likely to develop CINP.
Another way of interpreting our results is by looking at the 50% of patients who developed CINP vs. the other half who were treated with the same drug (paclitaxel) but did not develop CINP. Nearly one-quarter of the study sample were hypersensitive “double unlucky” by means of experiencing high levels of all related symptoms as well as developing CINP. This specific subgroup of patients needs greater attention to symptom evaluation and management and is the most challenging to treat. Early detection of symptoms, together with careful dose selection and assessment of early stages in the development of NP, are essential for preventing the simultaneous occurrence of severe multiple symptoms and CINP. Prevention of toxic neuropathies is most important. The overall management of patients with CINP encompasses 3 steps: prevention by modifying drug regimens to minimize toxicity; restoration of function; and symptomatic treatment.45 One area of further investigation that will likely result in significant benefits for these patients focuses on pharmacogenetic studies exploring the genetic basis of individual responses to drugs. We believe that genetic predisposition may be the reason for the individual variability in symptom experience and the development of CINP. Further exploration of this important topic may promote the development of new symptomatic treatment and provide support for the concept of individualized therapy.