The Role of Pain in Head and Neck Cancer Recurrence and Survivorship

Objective  To examine pain, a common symptom in patients with head and neck cancer, and its relationship to recurrence and survivorship.

Design  Prospective, observational study.

Setting  Tertiary care institution.

Patients  A total of 339 patients with head and neck carcinomas who participated in the Department of Otolaryngology's Outcomes Assessment Project between February 28, 1998, and November 30, 2001. Of 355 patients enrolled during this period, 7 were omitted from the study because they presented with persistent disease and 9 were omitted owing to a lack of valid pain data. Data on health-related quality of life were collected from the remaining patients at diagnosis and then at 3, 6, 9, and 12 months after diagnosis.

Intervention  Administration of surveys and questionnaires.

Main Outcome Measures  The relationship of self-reported pain level with health-related quality of life during the first year, recurrence status, and 5-year disease-specific survivorship was determined through univariate and multivariate analyses.

Results  Pain was associated with age, general physical and mental health conditions, depressive symptoms, survival rate, and recurrence within the first year. The 5-year survival rate was 81.8% for patients with low posttreatment pain and 65.1% for those with high pain. Posttreatment pain and tumor site were independent predictors of recurrence. Pain level, age, and treatment modality were independent predictors of 5-year survival.

Conclusion  Because of its association with recurrence and survival, pain within the first year of treatment for head and neck cancer is an important symptom that should be appropriately monitored and managed during routine follow-up.

Pain is an important but infrequently analyzed symptom in head and neck cancer and may play a predictive role in recurrence and survivorship outcomes. From 50% to 60% of patients with head and neck cancer will experience moderate to severe pain.¹ This pain may be associated with the initial presentation, recurrence, or treatment of head and neck cancer.

In many circumstances, severe pain that is associated with the initial presentation of head and neck cancer is suggestive of more advanced disease.^2,3 The prevalence of pain among patients with advanced disease is 80% to 100%; almost all patients with head and neck cancer will experience some pain during the course of their disease.^4-6 In advanced head and neck cancer, pain is frequently multidimensional.^7-9 The abundant innervation of the head and neck predisposes patients with destructive lesions to nociceptive pain resulting from direct bone and soft tissue destruction as well as neuropathic pain owing to invasion of nerves and the inflammatory milieu adjacent to nerves.⁹ Bone involvement of the mandible, maxilla, and skull base may result in severe pain owing to direct bony destruction and the attendant inflammation.^3,7

The association of pain with recurrent head and neck cancer has been recognized, and, in some cases, pain may be the only indication of recurrent disease.¹⁰ Failure to investigate substantial changes in pain symptoms or new-onset pain that develops following treatment may potentially delay the diagnosis of recurrent disease. Unfortunately, the pain symptoms of many patients who have been treated for head and neck cancer are underappreciated.⁹ In addition, patients with head and neck cancer may have difficulty self-reporting pain to their medical care providers.¹¹

The relationships between pain and the presentation, recurrence, and treatment of head and neck cancer are recognized, but few studies have attempted to quantify these associations objectively.¹² This prospective study was designed to examine the association between posttreatment pain and recurrence as well as the 5-year survival rate among patients with head and neck cancer. The associations among patient, disease, and treatment variables and posttreatment pain were also evaluated. This study also permitted an objective assessment of the level of pain experienced by patients with head and neck cancer at presentation and during follow-up.

This study used data prospectively gathered from the University of Iowa's Head and Neck Cancer Outcomes Assessment Project, which has been approved by the institutional review board. Participants provide information about their health and health-related quality of life at diagnosis and then at 3, 6, 9, and 12 months after diagnosis. Although data are now collected for 20 years after diagnosis, during the study period, data collection for each patient was terminated after 1 year of follow-up. Additional data addressing patient, disease, and treatment characteristics are collected as part of this project, and information about recurrence and survival is routinely updated.

This study included patients who provided a valid pain score while enrolled in the Outcomes Assessment Project between February 28, 1998 (when the pain item was first administered), and November 30, 2001. During this period, the project enrolled 67.1% of eligible patients.

Self-reported pain was measured at diagnosis and at 3, 6, 9, and 12 months after diagnosis using a numeric rating scale. Patients were asked to indicate their average level of pain during the last 4 weeks using an ordinal scale, from 0 to 10. This single-item measure of pain, recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials committee following their 2005 review of the literature,¹³ is a sensitive assessment of intensity that is well understood by patients.¹⁴

In the analyses, these scores were presented as means or as the percentage of patients reporting no (0), low (1-3), intermediate (4-6), or high (7-10) levels of pain.¹⁵ As a reference, the smallest clinically relevant difference in pain scores detectable by our patients was calculated to be 0.55. This clinically relevant difference was estimated using a distribution-based method that was based on an SD of 2.735 for the 257 pretreatment pain scores provided by this study's patient sample.¹⁶

The health-related quality-of-life measures used in this study included patient-reported general health and depressive symptoms. Physical and mental general health conditions were quantified using the 36-Item Short-Form Health Survey (SF-36).^17,18 Responses to the 36 items were aggregated into composite physical and mental health scores, which were then grouped into quartiles based on published reference values for men and women aged 55 to 64 years, the mean age range of this patient population.¹⁹ The level of depressive symptoms was measured using the Beck Depression Inventory, a well-validated 21-item instrument. Published cut-off scores classify depressive symptoms as normal (0-9), mild (10-20), moderate (21-30), and severe (≥31).^20,21

The data were analyzed using SPSS statistical software, version 13.0 (SPSS Inc, Chicago, Illinois). Analyses investigating the association of posttreatment pain with case-mix, treatment, and outcome characteristics used scores representing the follow-up pain score reported farthest from diagnosis (6, 9, or 12 months) for patients whose cancer did not recur within the first year, or the posttreatment pain score obtained simultaneous to or before the follow-up clinic visit at which recurrence was diagnosed for patients whose cancer recurred within the first year.

To assess factors associated with pain, continuous variables were analyzed using Pearson bivariate correlations, and categorical variables were analyzed using independent-sample t tests (2 values) and analyses of variance (≥3 values).

Cox regression analyses were used to assess the role of pain as a predictor of recurrence within the first year and 5-year, disease-specific survival rates, while taking other possible influencing factors into consideration. For these analyses, pain was grouped into no/low (pain score, 0-3) and moderate/high (4-10) levels of pain. Using these 2 categories of pain ensured sufficient sample sizes in both groups. The Wilcoxon statistic was used to determine whether the difference in survival rates for patients in the 2 pain categories was statistically significant.

Of 355 patients enrolled in the Outcomes Assessment Project between February 28, 1998, and October 31, 2001, 7 (2.0%) were omitted because they presented with persistent disease and an additional 9 (2.5%) were omitted because they did not provide a valid pain score. Of the remaining 339 patients, 233 were predominantly men (68.7%) with a mean age of 60.8 years (Table 1). Most had primary disease (84.4%), advanced-stage disease (59.9%), and oral cavity (42.2%) or laryngeal (23.3%) tumors. Most received surgical treatment alone (37.2%) or combined with radiotherapy (37.7%).

Trends in pain level during the first year of follow-up are shown in Table 2. The mean pain level decreased from 2.7 at 3 months after diagnosis to 1.6 at 12 months. The percentage of patients who reported no pain increased from 45.9% at pretreatment to 61.4% at 12 months. However, the percentage of patients who reported high levels of pain remained relatively constant at about 10% during the follow-up period.

The remaining analyses included 191 of 339 patients (56.3%) who had sufficient data to determine whether cancer did or did not recur within the first 12 months after diagnosis and who provided pain scores during the appropriate time period (ie, the posttreatment follow-up visit at or before the clinic encounter at which the diagnosis of recurrent disease was made for patients whose disease recurred within the first year and at the 6-, 9-, or 12-month follow-up visit for patients whose disease did not recur during that time).

Univariate analyses indicated that a higher level of posttreatment pain was significantly associated (P < .05) with younger age, worse physical and mental general health, and a higher level of depressive symptoms (Table 3). The results also demonstrated an association between pain and recurrence. The mean pain score provided by patients at or before the diagnosis of recurrence within the first year was significantly greater than the mean of the last pain score provided by patients who were not diagnosed as having a recurrence within the first year (2.9 vs 1.4; P = .006).

Table 4 shows the results of the analysis to determine whether pain was an independent predictor of recurrence within 1 year of diagnosis. The multivariate analysis that included these 2 variables indicated that pain (P = .003) and tumor site (P = .03) were independent predictors of first-year recurrence. Patients who reported an intermediate or high level of pain were almost 4 times more likely to be diagnosed as having a recurrence within the first year than those who reported no or low pain.

The last 2 analyses examined the association between pain and survival rates. The Figure shows the results of a comparison of 5-year disease-specific survival rates for the 129 patients who reported no pain or a low level of pain and the 28 patients who reported an intermediate or high level of pain. Those in the no/low posttreatment pain group had a significantly higher 5-year survival rate than those in the intermediate/high pain group (81.8% vs 65.1%; P = .04).

A multivariate analysis was then performed to determine whether pain was an independent predictor of survival (Table 5). The results indicated that age, tumor site, treatment modality, and recurrence within 1 year were independently associated with disease-specific survival. Because recurrence, understandably a substantial predictor of survival, was shown in Table 4 to be significantly associated with posttreatment pain, this variable was removed from a subsequent multivariate analysis. When omitted, posttreatment pain, age, and type of treatment were the predictors of disease-specific survival.

Because recurrence within the first year had such a substantial effect on survival rates, and posttreatment pain was previously shown to be highly associated with recurrence within the first year, a second multivariate analysis was performed that excluded first-year recurrence status. In this second model, posttreatment pain was an independent predictor of survival in addition to age and stage (Table 5). Patients who reported an intermediate or high level of pain were 2½ times more likely to die within the first 5 years after diagnosis than those who reported no or low pain.

Last, because the high level of posttreatment pain reported by a subset of patients who were not diagnosed as having a recurrence within the first year could be owing to undetected, persistent disease, a post hoc analysis was performed to assess the likelihood of occult cancer in these individuals. The 5-year observed survival rates for the subset of patients who had a high level of posttreatment pain but who did not experience a recurrence within the first year were compared with rates for patients who did experience a recurrence within the first year as well as patients who did not experience a recurrence within the first year and did not have high levels of posttreatment pain. The 64.0% survival rate among patients with high levels of pain and no recurrence was significantly higher than the 18.5% rate for patients with high levels of pain whose disease did recur (P < .001) but quite similar to the 69.7% rate for patients who had neither pain nor a recurrence. This finding strongly suggests that undetected, persistent disease was not a predominant cause of posttreatment pain in patients who did not experience a recurrence within the first year.

The results of this study indicated that pain is a prevalent problem for patients with head and neck cancer, with 10% continuing to report severe pain 12 months after diagnosis. The importance of managing pain was demonstrated in a study that asked patients newly diagnosed with head and neck cancer to prioritize their desired treatment outcomes.²² The 3 most frequently ranked items were “being cured of cancer,” “living as long as possible,” and “having no pain.”^22(p163) However, it has also been shown that the presence of posttreatment pain has often been underreported by patients with head and neck cancer and marginalized by health care providers.¹¹

Another reason that proper management of pain is important is its effect on health-related outcomes. As shown in this study, high levels of pain were associated with worse physical and mental general health and higher levels of depressive symptoms. Severe pain is often accompanied by fatigue, nausea, and insomnia, which can have deleterious effects on physical health, and feelings of agitation, anger, and hopelessness are other adverse effects of severe pain that can contribute to poor mental health.²³ Also, according to Hendler,²⁴ virtually all patients who experience chronic pain are depressed. Although chronic pain can be a symptom of depression and anxiety, Hendler concluded that pain is the cause of the depression for most of these patients. This association has also been supported by studies of patients with cancer in which pain was correlated with depression and suicide.^25-27

The results of this study also demonstrated a significant association between pain and disease recurrence. This finding is consistent with research by Smit et al,¹⁰ who stated that 70% of patients with proven recurrent disease reported pain as the first symptom. The onset of pain or an increase in pain should therefore prompt an aggressive workup for recurrent disease, especially because an early diagnosis of recurrence may result in more favorable survival rates. Unfortunately, if pain is not routinely evaluated during follow-up, the effectiveness of using this symptom as an early warning sign of recurrent disease is greatly reduced.

One drawback of this study is that the single item used to capture pain did not discriminate between pain in the head and neck vs other bodily pain. It is unlikely that the results would have demonstrated an association between posttreatment pain and recurrence as well as survival rates if pain unrelated to the cancer were a substantial problem in this patient population. However, non–cancer-related health issues might have been one cause of the pain reported by the subgroup of patients with no recurrence for whom post hoc analyses suggested that occult disease was not the predominant cause of their pain.

A second drawback is the lack of information about comorbidities, which can influence pain and survival. However, the confounding effect that comorbid illness might have on the association between pain and survival was greatly reduced by the use of disease-specific survival rates in this study.

Last, although an increase in pain across time would be the best indicator of the association between pain and recurrence, such data are often not available for patients whose disease recurred within the first 12 months after diagnosis. Therefore, this study used levels of pain at a given point in time, which represented posttreatment pain simultaneous to or before the follow-up clinic visit at which recurrence was diagnosed for patients whose cancer recurred within the first year.

It is critical to monitor and manage patients' pain on a regular basis during routine oncologic surveillance. The Joint Commission’s requirement that pain be assessed as a “fifth vital sign”²⁸ may provide the means for documenting pain and identifying changes in pain levels across time. Although previously published results indicated that patients tend to underreport pain, this routine collection of self-reported pain data is usually done by an individual other than the physician, so patients might more freely communicate this complaint. Patients may also underreport pain because they have not been advised about expected pain levels during and after their cancer-directed treatment or about the importance of reporting any pain or discomfort that exceeds those expected levels.

In managing pain, lack of education may be the major obstacle because most health care professionals receive only a cursory and often incomplete education in dealing with this important aspect of patient care.²⁹ Health care providers should know that, when routine monitoring indicates abnormal pain (a new onset, an increase in severity, or a persistent pain that should have subsided), the first step should involve a detailed evaluation for recurrent disease. If no evidence of recurrence is identified, then proper management requires a continued monitoring of pain to assure that the patient receives appropriate levels of medication. The most effective pain management includes a multidisciplinary approach and a dedicated pain-management team.

The prevalence of posttreatment pain within the first year after diagnosis of head and neck cancer suggests that physicians are not adequately addressing this issue, even though pain is associated with health-related quality of life and recurrent disease. Appropriate monitoring can be accomplished through the routine collection of pain as the fifth vital sign. Proper treatment, including an initial workup for recurrent disease, should be provided using a comprehensive, multidisciplinary approach.

Correspondence: Gerry F. Funk, MD, Department of Otolaryngology, Head and Neck Surgery, University of Iowa Hospitals and Clinics, Room 21010, Pomerantz Family Pavilion, 200 Hawkins Dr, Iowa City, IA 52242 (gerry-funk@uiowa.edu).

Submitted for Publication: March 12, 2008; final revision received February 3, 2009; accepted February 6, 2009.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Scharpf, Karnell, Christensen, and Funk. Acquisition of data: Scharpf and Karnell Analysis and interpretation of data: Scharpf, Karnell, Christensen, and Funk. Drafting of the manuscript: Scharpf, Karnell, and Funk. Critical revision of the manuscript for important intellectual content: Scharpf, Karnell, Christensen, and Funk. Statistical analysis: Scharpf and Karnell. Obtained funding: Karnell, Christensen, and Funk. Administrative, technical, and material support: Scharpf, Karnell, Christensen, and Funk. Study supervision: Scharpf, Karnell, and Funk.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by grant R01 CA106908-01 from the National Institutes of Health, Office of Cancer Survivorship.

Previous Presentation: Results of this study were presented at the Annual Meeting of the American Society of Head and Neck Surgeons at the Combined Otolaryngology Spring Meetings; May 16, 2005; Boca Raton, Florida.

Additional Contributions: Amy Trullinger, BS, enrolled eligible patients and collected data for this study.