Abstract
Context
Few studies have examined the incidence and severity of treatment-induced neuropathic symptoms in patients across different cancer types.
Objectives
This study aimed to: 1) report the prevalence of numbness/tingling (N/T) and neuropathic pain in patients with colorectal cancer (CRC) vs. other cancers; 2) describe the prevalence of moderate to severe N/T by specific clinical variables; and 3) examine factors associated with the presence of these symptoms.
Methods
A total of 3106 outpatients with colorectal (n = 718), breast (n = 1544), lung (n = 524), or prostate (n = 320) cancer were enrolled at any point in their treatment. Assessments were conducted at the initial visit and 28–35 days later. Patients reported pain and N/T; clinicians reported mechanism of pain and ranked the top three symptoms causing difficulties.
Results
Moderate to severe N/T was higher in patients with CRC relative to other cancer types (25.8% vs. 17.1%, P < 0.001); 25% vs. 10.5% of clinicians rated N/T as a top three symptom for patients with CRC relative to other cancers (P < 0.001). The prevalence of neuropathic pain was comparable between patients with CRC and other cancers (P = 0.654). Patients with CRC, longer duration of cancer, prior therapy, on current therapy, older patients and patients of black race experienced worse N/T.
Conclusion
Patients with CRC experience significantly higher rates of N/T but comparable neuropathic pain, relative to patients with other cancers. Awareness of the prevalence and severity of neuropathic symptoms and their associated risk factors in this patient population is critical for both clinicians and patients.
Keywords: colorectal cancer, neuropathy, neuropathic pain, numbness/tingling, oxaliplatin
Introduction
Colorectal cancer (CRC) represents one of the most common solid tumor types in the U.S., with over 142,000 new cases estimated to occur in 2013.1 The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) established that the addition of oxaliplatin to a combination of infusional 5-fluorouracil (5-FU)/leucovorin within the FOLFOX (FOLinic acid, Fluorouracil, OXaliplatin) regimen meaningfully improves disease-free survival of patients after resection of stage III and high-risk stage II CRC. Since the publication of the MOSAIC data in 20042 and especially following an updated analysis showing a durable overall survival benefit for FOLFOX,3 it has become the standard of care to incorporate oxaliplatin into adjuvant chemotherapy for non-metastatic colon cancer that is node-positive or displays other unfavorable features at the time of resection.
Although the incorporation of oxaliplatin into adjuvant chemotherapy for patients with CRC has proved beneficial in extending disease-free survival, its use as standard therapy is complicated by its neurotoxic effects. Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment.4,5 In the initial MOSAIC cohort, there was a 92% incidence of neurosensory symptoms in patients receiving oxaliplatin, including acute symptoms associated with infusion; during treatment there was a 31.6% incidence of grade 2 sensory neuropathy6 and a 12.4% incidence of grade 3 sensory neuropathy.6 At six-month follow-up, 41% of patients reported some degree of neurosensory symptoms, with 29.5% and 23.7% demonstrating persistent symptoms at 12 and 18 months, respectively.2 Other studies have reported a 52–66% incidence of grade 2/3 neuropathy during treatment with oxaliplatin.5,7
Patients with CRC are not unique in their exposure to potentially neurotoxic chemotherapy. Other platinum-containing drugs and other classes of chemotherapy, notably the taxanes, also are associated with the risk of neuropathic pain and numbness/tingling (N/T). These medications can be used in the treatment of other common tumors, such as lung, breast, and prostate cancers.8
Results from the above studies underscore the importance of valid and reliable assessments of neuropathic symptoms (N/T and pain) in patients undergoing chemotherapeutic treatments,4 not only for CRC but also for other cancers. Few studies have examined the prevalence and severity of these symptoms in large patient samples or across different cancer types. Fewer still have incorporated patient-reported outcome measures to determine the true burden of neuropathy and examine its associated factors.
In light of the above, the objectives in the current study were to: 1) report the prevalence and severity of N/T and neuropathic pain in patients with CRC relative to other common cancer types (breast, lung, or prostate), usingg data from a large multicenter study; 2) examine how disease stage, chemotherapy, use of a glycemic control agent and comorbidity impact the prevalence of moderate to severe N/T in CRC patients, and 3) examine whether specific demographic and/or clinical variables might be associated with the presence of N/T and neuropathic pain in the overall patient sample.
Methods
Study Site and Participants
From March 2006 to May 2008, outpatients with any stage colorectal, breast, lung, or prostate cancer were enrolled from Eastern Oncology Cooperative Group (ECOG)-affiliated institutions, including six academic centers and 32 community clinics. All patients were enrolled in the Symptom Outcomes and Practice Patterns (SOAPP) study (www.ecogsoapp.org), a multicenter study of disease- and treatment-related symptoms experienced by cancer patients being followed on an outpatient basis. Eligible patients were 18 years or older, recipients of care at an ECOG-affiliated institution, willing to complete the follow-up survey, and cognitively competent to complete surveys. The study protocol was approved by the Institutional Review Board at each participating institution. All participants provided written informed consent.
Patients were recruited when they checked in for their clinic appointments, and completed symptom assessment at the initial visit and at a follow-up visit 28–35 days later. Patients reported all items according to their experience during the preceding 24 hours. Reasons for incomplete forms were documented on an Assessment Compliance Form. Patients who were too ill to complete the follow-up questionnaire were given the option to mail the forms to the treating clinic by day 42 after the initial visit.
Measures
Patients reported the severity of 19 symptoms, including pain and N/T (items #1 and #13, respectively), using the M. D. Anderson Symptom Inventory (MDASI),9 a widely used valid and reliable instrument. These symptoms were rated “at their worst” in the previous 24 hours on a scale from 0 to 10, with 0 representing “not present” and 10 representing “as bad as you can imagine.”
Clinicians reported mechanism of pain and ranked the top three symptoms causing difficulties for each patient via the Clinician-On-Study Form; the 22 potential areas of difficulty, of which the three most bothersome were to be ranked as worst, second worst, and third worst, were: pain, fatigue, nausea, disturbed sleep, being distressed (upset), dyspnea, cognitive difficulties, anorexia/cachexia, drowsiness, dry mouth, sad/depressed, vomiting, N/T, constipation, sore mouth, rash/pruritus, difficulty walking, lack of information, financial problems, family problems, existential worries, and spiritual problems. The “mechanism of pain” question is part of the revised Edmonton Staging System for classifying cancer pain.10 This question required the clinician to assess patients’ type of pain from among four choices: 1) no pain syndrome, 2) any nociceptive combination of visceral and/or bone or soft tissue pain, 3) neuropathic pain syndrome with or without any combination of nociceptive pain, and 4) insufficient information to classify.
Data on patient demographics and other clinical characteristics were collected at the initial assessment. Patients were specifically asked to rate “how much are you bothered by difficulties related to health problems other than cancer?” (0=not at all, 1=a little bit, 2=moderately, 3=quite a bit, 4=extremely) as a measure of their symptom burden from comorbidities.
Statistical Analysis
Patient-reported N/T was considered moderate to severe at a score of ≥ 5 on the MDASI.11 Patient-reported N/T was considered as one of the top three symptoms if the difference between the score for the most severe symptom and that for N/T was ≤ 2 points regardless of the existence of ties among symptoms. Clinician-reported N/T was considered as one of the top three symptoms if N/T was ranked in any of the first three places. Chi-square tests were used to compare the patient characteristics and neuropathic symptoms between patients with CRC versus other cancer types. The prevalence of moderate to severe N/T in patients with CRC was examined by specific clinical variables (e.g., comorbidities, use of glycemic control agents, and disease stage and chemotherapy) using Fisher's exact test.
Multivariable logistic models were fitted to identify baseline patient and disease characteristics that were associated with the presence of patient-reported moderate/severe N/T (Model 1), clinician-reported N/T as one of the top three symptoms for patients (Model 2), and clinician-reported neuropathic pain (Model 3) at the initial assessment. A set of 15 variables were included as covariates in each of the three logistic models (disease site, age, years since diagnosis, race/ethnicity, disease status, advanced disease, ECOG performance status, weight loss in the past six months, prior systemic treatment, prior radiotherapy, current treatment, any counseling service, any support group, and current medications). The Variance Inflation Factor (VIF) was used to check multicollinearity among these variables and the largest VIF value was <3. A separate category for missing data was generated for categorical covariates if the proportion of data missing was no less than 5%. Patients with missing data on covariates were excluded from the logistic models. Clustered sandwich estimators of standard errors were used in the logistic models to account for the clustering effect of institutions.
No adjustment was made for multiple comparisons. All reported P-values are two-sided and were considered significant if less than 0.05. STATA 11·2 software was used for all data analysis12.
Results
Patients
In total, 3106 patients were enrolled in the study (718 with CRC; 1544 with breast cancer; 320 with prostate cancer, and 524 with lung cancer). Patient demographics and clinical characteristics are summarized in Table 1.
Table 1.
Patient Demographic and Clinical Characteristics
| Variables | Colorectal | Others (n=2388) | P-value | ||
|---|---|---|---|---|---|
| No. of patients | % | No. of patients | % | ||
| Age at study entry (mean, SD) | 61.6 | 12.7 | 61.1 | 12.3 | 0.372 |
| Years since diagnosis (mean, SD) | 1.9 | 2.2 | 3.3 | 4.5 | <0.001 |
| Gender | <0.001 | ||||
| Female | 346 | 48.2 | 1824 | 76.4 | |
| Male | 372 | 51.8 | 23.6 | 23.6 | |
| Race | 0.184 | ||||
| White | 599 | 84.3 | 2049 | 86.9 | |
| Black | 98 | 13.8 | 266 | 11.3 | |
| Others | 14 | 2.0 | 43 | 1.8 | |
| Ethnicity | <0.001 | ||||
| Non-Hispanic | 583 | 81.2 | 1989 | 83.3 | |
| Hispanic | 93 | 13.0 | 192 | 8.0 | |
| Unknown | 42 | 5.9 | 207 | 8.7 | |
| Disease status | 0.038 | ||||
| Complete response | 243 | 34.0 | 914 | 38.5 | |
| Partial response | 28 | 3.9 | 119 | 5.0 | |
| Stable disease | 324 | 45.4 | 1012 | 42.7 | |
| Progressive disease | 119 | 16.7 | 327 | 13.8 | |
| Disease stage | <0.001 | ||||
| Non-advanced | 377 | 52.7 | 1544 | 64.9 | |
| Advanced | 339 | 47.4 | 835 | 35.1 | |
| ECOG PS | <0.001 | ||||
| 0 | 375 | 52.3 | 1380 | 58.1 | |
| 1 | 299 | 41.7 | 806 | 34.0 | |
| 2–4 | 43 | 6.0 | 188 | 7.9 | |
| Weight loss in the prior 6 months | <0.001 | ||||
| <5 | 565 | 79.4 | 2066 | 87.6 | |
| >=5% | 147 | 20.7 | 292 | 12.4 | |
| Prior systemic therapy | 0.122 | ||||
| No | 294 | 41.0 | 901 | 37.8 | |
| Yes | 424 | 59.1 | 1486 | 62.3 | |
| Prior radiation therapy | <0.001 | ||||
| No | 550 | 77.1 | 1232 | 52.1 | |
| Yes | 163 | 22.9 | 1134 | 47.9 | |
| Current therapy | 0.110 | ||||
| No | 203 | 28.3 | 604 | 25.3 | |
| Yes | 515 | 71.7 | 1784 | 74.7 | |
| Any individual counseling service | 0.655 | ||||
| No | 649 | 90.8 | 2146 | 90.2 | |
| Yes | 66 | 9.2 | 233 | 9.8 | |
| Participate in any support group | 0.162 | ||||
| No | 676 | 94.6 | 2214 | 93.1 | |
| Yes | 39 | 5.5 | 165 | 6.9 | |
| # of medicines currently taken | 0.002 | ||||
| 0–4 | 242 | 33.7 | 658 | 27.6 | |
| 5–9 | 268 | 37.3 | 940 | 39.4 | |
| >=10 | 131 | 18.3 | 556 | 23.3 | |
| Unknown | 77 | 10.7 | 234 | 9.8 | |
SD = standard deviation;ECOG PS = Eastern Cooperative Oncology Group performance status.
Prevalence and Severity of N/T and Neuropathic Pain
Patient-reported moderate to severe N/T at the initial assessment was significantly higher in those with CRC relative to other cancer types (25.8% vs. 17.1%, P < 0.001) (Table 2). This trend persisted at the follow-up assessment (25.6% vs. 17.7%, P < 0.001). Of the clinicians, 25.1% rated N/T as one of the top three symptoms causing difficulties for patients with CRC (relative to 10.5% for patients with other cancer types). The prevalence of neuropathic pain was comparable between patients with CRC and other cancers (P = 0.654).
Table 2.
Prevalence and Severity of Numbness/Tingling and Neuropathic Pain in Patients with Colorectal Cancer Relative to Other Cancer Types (Breast, Lung or Prostate)
| Variable (based on patient or clinician report) | Colorec | Others | |||
|---|---|---|---|---|---|
| No. of patients |
% | No. of patients |
% | P-value | |
| Numbness/tingling at initial assessment - patient | <0.001 | ||||
| <5 | 526 | 74.2 | 1966 | 82.9 | |
| ≥5 | 183 | 25.8 | 405 | 17.1 | |
| Numbness/tingling is the most severe symptom at initial assessment - patient a | <0.001 | ||||
| No | 512 | 72.2 | 1963 | 82.8 | |
| Yes | 197 | 27.8 | 408 | 17.2 | |
| Numbness/tingling is one of the top 3 symptoms at initial assessment - patient b | <0.001 | ||||
| No | 317 | 44.7 | 1413 | 59.6 | |
| Yes | 392 | 55.3 | 958 | 40.4 | |
| Numbness/tingling at follow-up – patient | <0.001 | ||||
| <5 | 495 | 74.4 | 1744 | 82.3 | |
| ≥5 | 170 | 25.6 | 376 | 17.7 | |
| Numbness/tingling is one of top 3 symptoms at initial assessment-clinician | <0.001 | ||||
| No | 538 | 74.9 | 2137 | 89.5 | |
| Yes | 180 | 25.1 | 251 | 10.5 | |
| Pain is one of the top 3 symptoms at initial assessmen -clinician | <0.001 | ||||
| No | 507 | 70.6 | 1512 | 63.3 | |
| Yes | 211 | 29.4 | 876 | 36.7 | |
| Neuropathic pain at initial assessment – clinician | 0.654 | ||||
| No | 544 | 91.3 | 1651 | 90.7 | |
| Yes | 52 | 8.7 | 170 | 9.3 | |
Patients reported the severity of 19 symptoms using the MDASI (numbness/tingling, pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, problem with remembering, lack of appetite, drowsy, dry mouth, sad, vomiting, diarrhea, constipation, sore mouth, skin rash, hair loss and coughing). There were many ties in the symptom scores (range: 0–10) reported by patients. As long as the numbness/tingling score was no smaller than the score for any other symptom, numbness/tingling was considered as the most severe symptom for the patient.
Patient-reported numbness/tingling was considered as one of the top 3 symptoms if the difference between the score for the most severe symptom and that for numbness/tingling was ≤ 2 points regardless of the existence of ties among symptoms.
Among patients with CRC, those who were extremely bothered by comorbidities had the highest prevalence of moderate to severe N/T, followed by progressively less N/T indicated in those who were moderately or not bothered by comorbidities (Fig. 1). The use of a glycemic control agent was not significantly associated with increased levels of moderate to severe N/T in patients with CRC (25.9% in those who took such an agent vs. 25.8% in those who did not [P = 0.99, Fig. 1]). Those with metastatic disease and concurrent chemotherapy reported the highest percentage of moderate to severe N/T relative to patients with localized disease and no chemotherapy (30.0% vs. 11.8%).
Figure 1.
Percentages of numbness/tingling as one of clinician-rated top 3 symptoms and percentages of patient-reported moderate to severe numbness/tingling in patients with colorectal cancer (n = 709) by different clinical factors at the initial assessment
The proportion that clinicians rated N/T as one of top three symptoms was highest for CRC patients with localized disease currently undergoing chemotherapy (29.2%), followed closely by patients with metastatic disease undergoing chemotherapy (27.8%), and lowest for patients with localized disease who did not undergo chemotherapeutic treatment (11.1%). There was no significant difference in this proportion between CRC patients who used a glycemic control agent vs. those who did not (18.8% vs. 25.9%, P = 0.16) (Fig. 1).
Factors Associated with the Presence of N/T and Neuropathic Pain at the Initial Assessment
Patients with CRC had significantly higher odds for experiencing moderate to severe N/T compared to patients with other cancer types at the initial assessment (adjusted odds ratio [OR]=1.66, 95% confidence interval [CI] 1.34, 2.05, P < 0.001). Other statistically significant factors for this outcome included increasing age, greater number of years since diagnosis, being of black race, having an ECOG PS > 0, having had prior systemic therapy, and being on a higher number of concurrent medications (Model 1, Table 3).
Table 3.
Patient and Disease Characteristics Associated with the Presence of Numbness/Tingling at the Initial Assessment
| Model 1 Outcome: ≥5 Numbness/ Tingling (n=2910a) |
Model 2 Outcome: Numbness/Tingling Rated as One of Top 3 Symptoms by Clinician (n=2925b) |
||||||
|---|---|---|---|---|---|---|---|
| Variables | Levels | OR | 95% CI | P-value | OR | 95% CI | P-value |
| Disease site | Colorectal vs. others | 1.66 | 1.34–2.05 | <0.001 | 2.95 | 2.07–4.19 | <0.001 |
| Age (yrs) | Continuous | 0.99 | 0.98–1.00 | 0.007 | 1.00 | 0.99–1.01 | 0.998 |
| Years since diagnosis | Continuous | 1.02 | 1.00–1.04 | 0.036 | 1.01 | 0.98–1.03 | 0.671 |
| Race | Black v. White | 2.02 | 1.55–2.63 | <0.001 | 1.22 | 0.75–1.98 | 0.426 |
| Other v. White | 2.18 | 1.28–3.70 | 0.004 | 0.74 | 0.33–1.66 | 0.468 | |
| Ethnicity | Non-Hispanic v Hispanic | 1.66 | 0.97–2.82 | 0.064 | 0.74 | 0.33–1.67 | 0.467 |
| Unknown v Hispanic | 0.38 | 0.26–0.56 | <0.001 | 0.72 | 0.46–1.13 | 0.153 | |
| Disease status | PR v CR | 0.92 | 0.57–1.47 | 0.724 | 1.16 | 0.69–1.97 | 0.569 |
| SD v CR | 0.90 | 0.67–1.21 | 0.489 | 0.93 | 0.69–1.25 | 0.626 | |
| PD v CR | 0.88 | 0.61–1.28 | 0.512 | 0.64 | 0.37–1.08 | 0.095 | |
| Advanced disease | Yes v No | 1.24 | 0.94–1.65 | 0.133 | 1.15 | 0.81–1.63 | 0.444 |
| ECOG PS | 1 v 0 | 1.99 | 1.52–2.63 | <0.001 | 1.37 | 1.00–1.88 | 0.047 |
| 2–4 v 0 | 3.28 | 2.16–4.99 | <0.001 | 1.21 | 0.76–1.92 | 0.430 | |
| Weight loss | >5% v ≤5% | 0.97 | 0.70–1.34 | 0.846 | 0.70 | 0.48–1.02 | 0.061 |
| Prior systemic treatment | Yes v No | 1.48 | 1.18–1.86 | 0.001 | 1.30 | 1.04–1.62 | 0.023 |
| Prior radiotherapy | Yes v No | 0.97 | 0.80–1.20 | 0.807 | 0.95 | 0.75–1.21 | 0.696 |
| Current treatment | Yes v No | 1.05 | 0.85–1.31 | 0.647 | 1.55 | 1.21–1.98 | <0.001 |
| Any counseling service | Yes v No | 1.17 | 0.76–1.82 | 0.476 | 1.05 | 0.72–1.51 | 0.814 |
| Any support group | Yes v No | 0.90 | 0.61–1.31 | 0.574 | 0.85 | 0.46–1.56 | 0.598 |
| Medicine currently taken | 5–9 v 0–4 | 1.38 | 1.09–1.73 | 0.006 | 1.11 | 0.84–1.46 | 0.474 |
| ≥10 v 0–4 | 1.73 | 1.31–2.30 | <0.001 | 0.95 | 0.66–1.36 | 0.768 | |
| Unknown v 0–4 | 1.07 | 0.69–1.66 | 0.763 | 1.08 | 0.71–1.65 | 0.713 | |
ECOG PS = Eastern Cooperative Oncology Group performance status; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.
Of the 3106 patients, 3080 of them reported a numbness/tingling score at the initial assessment. Of the 3080 patients with numbness/tingling data, 170 patients had missing values for at least one of the covariates, and 2910 patients were included in this regression model.
Of the 3106 patients, 181 patients had missing values for at least one of the covariates, and 2925 patients were included in this regression model.
Patients with CRC were nearly three times more likely to have N/T ranked by clinicians as one of top three symptoms causing difficulties for them, relative to patients with other cancer types (adjusted OR=2.94, 95% CI 2.07, 4.19, P < 0.001). ECOG PS 1 vs. 0, prior systemic therapy and currently being on therapy were other significant factors (Model 2, Table 3). There was no statistically significant association between disease site and neuropathic pain as reported by clinicians (adjusted OR=0.94, 95% CI 0.67, 1.33, P=0.745).
Symptom Worsening Between Initial and Follow-Up Assessments
Notably, from among patients with any cancer type who were currently receiving cancer treatment and reported no N/T at the initial assessment, 4.8% (48 of 991 for whom data were available) reported newly emergent moderate to severe N/T at the follow-up assessment. Further, from among those who were currently receiving cancer treatment and reported mild N/T at the initial assessment (677 patients), nearly a fifth (19.2%) reported worsening or moderate to severe N/T at the follow-up assessment. There was no significant difference between patients with CRC and other cancer types with respect to the proportion of worsening N/T between the two assessments.
Among CRC patients only, 7% (53 of 718) were reported by clinicians as not having N/T as one of the top three symptoms causing difficulties at the initial assessment, but as being among the top three causing difficulties at the follow-up assessment. Conversely, 79 patients (9.7%) were reported by clinicians as having N/T as one of the top three symptoms at the initial assessment, but not at the follow-up assessment. N/T was rated among the top three symptoms at both assessments for 101 (14.1%) patients.
Discussion
To our knowledge, this is one of the largest, multicenter studies to present a comparative analysis of the prevalence and severity of treatment-induced neuropathic symptoms and their risk factors in patients with colorectal versus breast, lung, or prostate cancer, with data collected prospectively using patient-reported outcomes. Our results indicate that patients with CRC experience significantly higher rates of moderate to severe N/T relative to patients with breast, lung, or prostate cancer, and that N/T is more likely to be one of top three symptoms causing difficulties specifically for CRC patients. These results concur with previous findings reported in abstract form, which indicate that among CRC patients undergoing FOLFOX chemotherapy, N/T is consistently among the five most severe patient-reported symptoms.13 Our results further indicated that CRC patients – whether with primary or metastatic disease – had higher rates of moderate to severe N/T if they had had prior chemotherapy or were on concurrent therapy relative to patients who had undergone no therapy, providing additional proof that increasing exposure to certain types of chemotherapy is related to increasing neurotoxicity. The reporting of newly emergent N/T, as well as worsening N/T at the follow-up assessment, by patients with any cancer type who were currently receiving cancer treatment (and who reported no N/T at the initial assessment) provides further support to this conclusion. The finding that neuropathic pain was not significantly different between CRC patients and those with other cancer types reinforces that N/T may not be synonymous with painful neuropathy. Indeed, previous research13 indicates that N/T generally presents earlier (on the order of weeks to months) relative to neuropathic pain in the course of oxaliplatin therapy and it – rather than neuropathic pain – is generally the dose-limiting factor during the course of treatment.13,14 In paclitaxel-induced neuropathy, N/T is more prominent than is pain.15 Additionally, patients who participated in a recent clinical trial of an investigational therapy for established chemotherapy-induced neuropathy reported substantially more N/T than neuropathic pain.16
In examining the demographic and clinical variables that may be predisposing patients to worse neuropathic outcomes, our results indicated that patients with CRC (relative to other cancers), older patients, those with longer duration of cancer, poor performance status, on prior systemic or current therapy, on a higher number of concurrent medications, and of black race are significantly more likely to experience worse numbness/tingling. Without more granular data, it is admittedly impossible to exclude confounding, e.g., a longer duration of cancer leading to more cumulative exposure of a given patient to neurotoxic chemotherapy. Nonetheless, patients expecting to have rapid symptomatic recovery during or after treatment may benefit from awareness of these potential factors. Clinician awareness of patients who may be at increased risk for worse outcomes is equally crucial. Previous observational studies have demonstrated clinicians’ strong preferences for using oxaliplatin when selecting the first-line treatment regimen for patients with advanced CRC.17,18 In light of the current results, and in weighing treatment risks versus benefits, clinicians may want to consider non-platinum containing chemotherapy regimens with similar or equal efficacy as oxaliplatin, if and when available, particularly for vulnerable patients. Results from recent trials examining taxane or paclitaxel-induced neuropathy confirm that certain patients groups are indeed more likely to experience worse neuropathic outcomes. In particular, a recent breast cancer trial examining taxane-induced neuropathy indicated that women of African-American descent are at twice the risk of chemotherapy-induced peripheral neuropathy (CIPN) relative to White women (hazard ratio 2.1, P = 4.5 × 10−11)19. In another study, women receiving paclitaxel for non-metastatic breast cancer were reported to have a greater than threefold risk of dose limiting CIPN relative to White women (hazard ratio 3.35, 95% CI 1.54, 7.28).20 These data, along with our study, provide further evidence of the racial susceptibility of African Americans to CIPN and the need for both a better understanding of the biological basis of this susceptibility as well as effective management strategies for these and other at-risk patients.
The SOAPP study was not specifically designed for investigating neuropathy in CRC patients as a primary outcome. As such, there are some important limitations to our current analyses. The MDASI21 contains a single question about N/T, whereas other tools like the European Organization for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy-20 and the Functional Assessment of Cancer Therapy- Gynecologic Oncology Group-Neurotoxicity provide more nuanced measurements of patient-reported neuropathic outcomes. Also, detailed information about specific chemotherapy regimens or patients’ exposure to oxaliplatin was not collected in our study; consequently, we cannot claim that this is specifically a study of CIPN. However, we presume that, after the publication of the MOSAIC trial2 and the widespread adoption of the FOLFOX regimen by practitioners, most CRC patients who received multi-agent chemotherapy in our study would have been exposed to oxaliplatin.
An additional limitation consequent to this presumption is that we cannot be certain in regard to when patients may have been exposed to oxaliplatin; thus, we do not have information either on the specific types of (potentially) oxaliplatin-induced neuropathy or their individual time courses of manifestation. This is important to mention because oxaliplatin can cause two distinct forms of neuropathy: an acute syndrome likened to neuromyotonia that can involve extreme sensitivity to cold and distal, perioral and pharyngolaryngeal dysesthesias; and a chronic sensory axonal neuropathy in a stocking-glove distribution.4 The timing of clinical evaluations of patients currently receiving treatment presumably occurred as they were ending one cycle of chemotherapy and beginning the next, making it less likely that acute effects were being assessed.
A lack of anatomical detail about the location of symptoms makes it impossible to comment on the possibility of other contributing factors to neuropathic pain, such as radiation, surgery, or the site of the cancer itself. However, this may matter less in assessing neuropathic pain in CRC patients vs. those with other tumor types that have better defined postoperative pain syndromes, e.g., post-thoracotomy pain in lung cancer or post-mastectomy pain in breast cancer.
Another limitation of our study is that data on comorbidities were not directly available, although data were collected on the extent to which each patient was bothered by comorbidities as well as on concomitant medication use. Contrary to a previous study,13 which indicates that a diagnosis of diabetes may be related to a higher severity of N/T, the current data did not find the prescription of glycemic control agents to be associated with an increased risk of moderate to severe N/T. Of note, however, the use of a glycemic control agent served as a surrogate variable in our study; we did not have definitive knowledge of patients’ formal diagnosis of diabetes.
The management of CIPN continues to be a significant challenge both for patients and clinicians, and efforts to prevent the development of neurotoxicity have thus far largely been unsuccessful. A recent randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium to prevent oxaliplatin-induced sensory neurotoxicity reported that it did not demonstrate any activity as a neuroprotectant against oxaliplatin-induced chemotherapy.22 Another recent randomized trial of acetyl-L-carnitine (ALC) for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast therapy reported a lack of evidence that ALC affected CIPN at 12 weeks; however, it significantly increased CIPN by 24 weeks,23 leading its authors to recommend that patients should be discouraged from using supplements without proven efficacy. As it stands, there is no robust evidence to support the use of nutraceuticals in preventing or treating CIPN.
As reported in another paper about neuropathy using the E2Z02 data,24 whereas we did not collect specific medicines used to treat neuropathic pain, we had access to information about drug classes. Interestingly, the issuance of prescriptions for nerve pain in patients with ≥5 N/T trended toward lower rates of use in CRC patients vs. those with other tumor types.24
The unique contribution of the current study is its comparative examination of treatment-induced neuropathic symptoms (N/T and pain) in oncology outpatients with CRC versus other cancers, and its identification of patients potentially at higher risk for worse neuropathic outcomes. Clinician awareness of patient differences in the severity of, and susceptibility to, neuropathic symptoms is crucial in order to inform appropriate treatment management strategies - and where possible, ameliorative interventions - for at-risk patients. The association of N/T and neuropathic pain with patient-reported qualify of life and clinician-reported difficulty in caring for these patients are addressed in another paper using the same data.24
Acknowledgments
This study was supported in part by Public Health Service Grants CA37604, CA17145, and grants from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Drs. Fisch and Zhao had full access to the data.
Footnotes
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Data from this paper were presented as an oral abstract at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 6, 2011.
Disclosures
The authors have no disclosures.
References
- 1.Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi: 10.3322/caac.21166. [DOI] [PubMed] [Google Scholar]
- 2.André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351. doi: 10.1056/NEJMoa032709. [DOI] [PubMed] [Google Scholar]
- 3.André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–3116. doi: 10.1200/JCO.2008.20.6771. [DOI] [PubMed] [Google Scholar]
- 4.Bennett BK, Park SB, Lin CS, et al. Impact of oxaliplatin-induced neuropathy: a patient perspective. Support Care Cancer. 2012;20:2959–2967. doi: 10.1007/s00520-012-1428-5. [DOI] [PubMed] [Google Scholar]
- 5.Argyriou AA, Cavaletti G, Briani C, et al. Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer. Cancer. 2013;119:438–444. doi: 10.1002/cncr.27732. [DOI] [PubMed] [Google Scholar]
- 6.Range F, Moslinger H, Viranyi Z. Domestication has not affected the understanding of means-end connections in dogs. Anim Cogn. 2012;15:597–607. doi: 10.1007/s10071-012-0488-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Vincenzi B, Frezza AM, Schiavon G, et al. Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV. Support Care Cancer. 2013;21:1313–1319. doi: 10.1007/s00520-012-1667-5. [DOI] [PubMed] [Google Scholar]
- 8.Kudlowitz D, Muggia F. Defining risks of taxane neuropathy: insights from randomized clinical trials. Clin Cancer Res. 2013;19:4570–4577. doi: 10.1158/1078-0432.CCR-13-0572. [DOI] [PubMed] [Google Scholar]
- 9.Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000;89:1634–1646. doi: 10.1002/1097-0142(20001001)89:7<1634::aid-cncr29>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
- 10.Fainsinger RL, Nekolaichuk CL, Lawlor PG, et al. A multicenter study of the revised Edmonton Staging System for classifying cancer pain in advanced cancer patients. J Pain Symptom Manage. 2005;29:224–237. doi: 10.1016/j.jpainsymman.2004.05.008. [DOI] [PubMed] [Google Scholar]
- 11.Serlin RC, Mendoza TR, Nakamura Y, et al. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61:277–284. doi: 10.1016/0304-3959(94)00178-H. [DOI] [PubMed] [Google Scholar]
- 12.StataCorp. Stata Statistical Software: Resease 11. College Station: TX: StataCorp LP; 2009. [Google Scholar]
- 13.Wang XS, Fogelman DR, Eng C, et al. Prospective study of paresthetic neurotoxicity from oxaliplatin-based regimens in the treatment of colorectal cancer. J Clin Oncol. 2010;28(Suppl) abstr 3585. [Google Scholar]
- 14.Romanus D, Weiser M, TerVeer A, et al. How often is aduvant FOLFOX discontinued for toxicity among colon cancer patients in the routine care setting? J Clin Oncol. 2009;27(Suppl) abstr 9530. [Google Scholar]
- 15.Loprinzi CL, Reeves BN, Dakhil SR, et al. Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1. J Clin Oncol. 2011;29:1472–1478. doi: 10.1200/JCO.2010.33.0308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wolf SL, Barton DL, Qin R, et al. The relationship between numbness, tingling, and shooting/burning pain in patients with chemotherapy-induced peripheral neuropathy (CIPN) as measured by the EORTC QLQ-CIPN20 instrument, N06CA. Support Care Cancer. 2012;20:625–632. doi: 10.1007/s00520-011-1141-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zafar SY, Marcello JE, Wheeler JL, et al. Longitudinal patterns of chemotherapy use in metastatic colorectal cancer. J Oncol Pract. 2009;5:228–233. doi: 10.1200/JOP.091010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Eng C, Kopetz S. Commentary: practice patterns and potential impact on quality measures for a practicing physician. J Oncol Pract. 2009;5:233–235. doi: 10.1200/JOP.091013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Schneider BP, Li L, Miller K, et al. Genetic associations with taxane-induced neuropathy by a genome-wide association study (GWAS) in E5103. J Clin Oncol. 2011;29(Suppl) abstr 1000. [Google Scholar]
- 20.Speck RM, Sammel MD, Farrar JT, et al. Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer. J Oncol Pract. 2013;9:e234–e240. doi: 10.1200/JOP.2012.000863. [DOI] [PubMed] [Google Scholar]
- 21.Cleeland CS, Zhao F, Chang VT, et al. The symptom burden of cancer: evidence for a core set of cancer-related and treatment-related symptoms from the Eastern Cooperative Oncology Group Symptom Outcomes and Practice Patterns study. Cancer. 2013;119:4333–4440. doi: 10.1002/cncr.28376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance) J Clin Oncol. 2014;32:997–1005. doi: 10.1200/JCO.2013.52.0536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013;31:2627–2633. doi: 10.1200/JCO.2012.44.8738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Jones D, Zhao F, Brell J, et al. Neuropathic symptoms, quality of life, and clinician perception of patient care in medical oncology outpatients with colorectal, breast, lung, and prostate cancer. J Cancer Surviv. 2014 Jul 15; doi: 10.1007/s11764-014-0379-x. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]