Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer: A prospective analysis using the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module

Authors


  • Presented in part at the American Society for Radiation Oncology (ASTRO) 52nd Annual Meeting; October 31-November 4, 2010; San Diego, CA.

  • We extend special thanks to Christine F. Wogan for editorial comments.

Abstract

BACKGROUND

A prospective longitudinal study to profile patient-reported symptoms during radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) for head and neck cancer was performed. The goals were to understand the onset and trajectory of specific symptoms and their severity, identify clusters, and facilitate symptom interventions and clinical trial design.

METHODS

Participants in this questionnaire-based study received RT or CCRT. They completed the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module before and weekly during treatment. Symptom scores were compared between treatment groups, and hierarchical cluster analysis was used to depict clustering of symptoms at treatment end. Variables believed to predict symptom severity were assessed using a multivariate mixed model.

RESULTS

Among the 149 patients studied, the majority (47%) had oropharyngeal tumors, and nearly one-half received CCRT. Overall symptom severity (P < .001) and symptom interference (P < .0001) became progressively more severe and were more severe for those receiving CCRT. On multivariate analysis, baseline Eastern Cooperative Oncology Group performance status (P < .001) and receipt of CCRT (P < .04) correlated with higher symptom severity. Fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food were more severe for those receiving CCRT. Both local and systemic symptom clusters were identified.

CONCLUSIONS

The findings from this prospective longitudinal study identified a pattern of local and systemic symptoms, symptom clusters, and symptom interference that was temporally distinct and marked by increased magnitude and a shift in individual symptom rank order during the treatment course. These inform clinicians about symptom intervention needs, and are a benchmark for future symptom intervention clinical trials. Cancer 2014;120:1975–1984. © 2014 American Cancer Society.

INTRODUCTION

Radiotherapy (RT), an essential treatment of head and neck malignancies, is associated with a variety of acute and late toxicities and associated symptoms that affect various normal tissues and organ systems and interfere with patient activities and functionality. Working groups have emphasized the importance of using patient-reported outcome (PRO) measures rather than relying on physician ratings of toxicity in clinical effectiveness research.[1, 2] The use of patient symptom assessment tools has been recommended by the US National Institutes of Health for optimal patient care,[3] and are more representative of symptom burden and therefore are now preferred over quality-of-life instruments.[1] Comprehensive routine symptom assessment and effective symptom management are particularly important during the course of RT, with or without concurrent chemotherapy (chemoradiotherapy [CCRT]), for head and neck cancer. Unrecognized or uncontrolled symptoms lead to substantial distress and unnecessary suffering. Furthermore, a high symptom burden may lead to poorer tolerance of therapy, unplanned treatment interruptions, or modification of the overall treatment schedule, which may negatively affect oncologic outcomes and worsen prognosis.[4]

Certain acute symptoms resolve after therapy, others may persist and become chronic (“consequential late toxicity”), and yet other toxicity-associated symptoms may emerge months or even years after recovery from acute symptoms and are more prone to increase over time.[5] It is only within the last decade or so that the shift toward greater primary RT-based treatment and now commonplace CCRT has made us more acutely aware of the potential toxicity costs to patients. However, to our knowledge, the pattern of patient-reported local and systemic symptoms during the treatment of head and neck cancer has not been fully detailed in a prospective longitudinal study.

The University of Texas MD Anderson Cancer Center Symptom Inventory (MD Anderson Symptom Inventory) is a validated multisymptom assessment instrument that evaluates patient symptoms commonly associated with cancer and cancer therapy, and the interference with activities of daily living. Because patients with head and neck cancer have distinct disease site-related and treatment-related symptoms, the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) was developed and validated to assess specific head and neck symptoms,[6] including those associated with mucositis, such as dry mouth, lack of appetite, pain, mouth/throat sores, problem tasting food, problem with mouth/throat mucus, and difficulty chewing/swallowing.[7] The MDASI-HN takes approximately 2 minutes to complete, and affords clinicians brief, pertinent, and easily attainable patient reported data to help guide patient-specific interventions, to monitor the success of interventions, and to use in comparative outcomes research. We have previously described the symptom profile of patients with head and neck cancer both before RT-based treatment has begun[8]and toward the end of treatment[7]and modeled patient group-based symptom severity differences and trajectories,[9] but understanding the timing of onset and trajectory of the severity and resolution of specific symptoms associated with RT or CCRT is necessary for developing programmatic symptom prevention and intervention strategies and for the rational design of symptom intervention clinical trials.

To address this need, the specific goals of the current study using weekly symptom assessments were to 1) characterize the pattern of acute symptoms, both local and systemic, reported by patients with head and neck cancer during RT or CCRT; 2) evaluate the symptom profiles experienced by selected patient subgroups (RT or CCRT); and 3) identify potential patient-, tumor-, and treatment-related factors associated with symptom severity.

MATERIALS AND METHODS

Patients

This single-institution, prospective, questionnaire-based study was conducted after Institutional Review Board approval. Consecutive patients who were able to read and understand English and were scheduled to undergo RT or CCRT for head and neck cancer with curative intent were recruited in our RT planning and quality assurance clinic.[10] All participants provided study-specific informed consent and were enrolled before any radiation-based treatment was initiated. Patient demographic and clinical variables were collected. Patient performance status before radiation-based treatment was rated by the treating radiation oncologist according to the Eastern Cooperative Oncology Group (ECOG) scale.[11] Tumor and lymph node classification was recorded according to the sixth edition of the American Joint Committee on Cancer staging system, published in 2002. Prior surgery and primary tumor site were coded as described elsewhere.[12] Exclusion criteria for this analysis were receipt of treatment with palliative intent, having distant metastatic disease, prior head and neck RT, prior index cancer treatment outside the study institution, and failure to complete at least 50% of the cumulative MDASI-HN items across all planned survey time points.

The MDASI-HN Assessment Tool

The MDASI-HN is a psychometrically validated 28-item questionnaire containing 13 “core” items representing important symptoms common to all cancer types, 9 “head and neck cancer-specific” items, and 6 questions regarding the extent to which the symptom complex interferes with activities of daily life (“interference” items).[6] The MDASI-HN symptom items are rated on numeric scales of 0 to 10 from “not present” to “as bad as you can imagine.” The 6 interference items are rated on numeric scales of 0 to 10 from “did not interfere” to “interfered completely.” Participating patients self-administered and completed the MDASI-HN questionnaires in hard copy before the initiation of radiation-based therapy (week 0) and then weekly during the 6-week to 7-week course of RT or CCRT.

Statistical Analysis

Descriptive statistics were used to summarize patient and clinical characteristics and MDASI-HN scores. The overall mean symptom severity and the mean values for each MDASI-HN item over the 6-week to 7-week treatment course were plotted for each treatment group (RT vs CCRT). To assist with the clinical interpretation of these data, the percentage of patients with moderate to severe (ratings of ≥ 5 on the scale of 0-10) and severe (ratings of ≥ 7) levels of the most common symptoms identified were also calculated, as were symptoms experienced at moderate to severe levels by at least 15% of patients at the end of treatment. Hierarchical cluster analysis of symptoms at the end of therapy was used to provide a pictorial representation of how symptoms clustered at that time. Group mean differences were compared with independent Student t tests. All reported P values are 2-tailed and considered significant if < .05, unless otherwise noted when Bonferroni corrections were used.

Correlates of higher symptom severity were based on the arithmetic average of the symptom items. Covariates that could influence symptom severity were prespecified and included sex, age, primary tumor site, T classification, N classification, receipt of previous treatment (surgery or chemotherapy), receipt of CCRT (vs RT), RT technique (3-dimensional conformal RT or intensity-modulated RT [IMRT]), and baseline (pretreatment) ECOG performance status. We first fitted linear mixed models with only time and a covariate at a time as fixed effects and patients as random effects to determine the independent effect of a covariate on the overall mean symptom severity. Covariates that were significant at a P value < .05 were entered as main effects in a multivariate mixed model that allowed us to examine the effect of the predictor variables simultaneously. Analyses were performed using IBM SPSS Statistics software (version 21.0; IBM, Armonk, NY).

RESULTS

Patients, Tumors, and Previous Treatment

Of the 161 patients enrolled in this longitudinal study from March 2006 to August 2007, 149 met the current criteria for analysis (77 treated with RT and 72 treated with CRT). The reasons for exclusion were prior RT to the head and neck (8 patients), treatment with palliative intent (3 patients), and receipt of prior outside treatment with limited medical records available (1 patient). Patient, tumor, and treatment characteristics are presented in Table 1. The median patient age was 59 years (standard deviation, 11.06 years). The majority of tumors (116 tumors) were of squamous histology. Thirty-eight patients received induction chemotherapy; the most common regimens were docetaxel, cisplatin, and 5-fluorouracil (15 patients) and a platinum-taxane doublet (15 patients). Seventy-two patients received CCRT; the most common systemic agent was cisplatin (38 patients), followed by cetuximab (16 patients), multiagent regimens (11 patients), and carboplatin (6 patients). The majority of the patients (92%) were treated with IMRT; the median radiation dose was 66 gray (Gy) (range, 56 Gy-72 Gy), delivered in a median of 30 fractions (range, 23 fractions-42 fractions) over a median of 41 days (range, 21 days-52 days). The majority of patients (87%) were treated with standard-fractionation RT schedules.

Table 1. Patient, Tumor, and Treatment Characteristics
CharacteristicsTotal (n=149)Concurrent Chemoradiation (n=72)Radiotherapy (n=77)
No.%No.%No.%
  1. Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Age,y      
<60795337514255
≥60704735493545
Sex      
Female392615212431
Male1107457795369
Educational level      
≤12th grade563826363039
>12th grade936246644761
Ethnicity      
White non-Hispanic1228264895875
Black non-Hispanic11734810
Hispanic11723912
Other533423
Employment status      
Employed outside the home805438534254
Homemaker433411
Retired483221292735
Medical leave of absence642345
Disabled by illness754634
Unemployed212300
Other212300
Disease site      
Oropharynx694742592736
Oral cavity18137101114
Nasopharynx535700
Larynx1396879
Hypopharynx644623
Thyroid/trachea8500811
Major salivary gland10723811
Nasal cavity/paranasal sinus1073479
Skin431134
Unknown primary site431134
ECOG performance status      
01026949695370
1382617242128
2645711
3110011
T classification      
TX/0/1/2865933465370
T3/4493337521216
Recurrent128111114
N classification      
NX/0/1634320284357
N2745145632939
N3645711
Recurrent321123
Prior treatment      
No prior treatment714842582938
Prior chemotherapy362422311418
Prior surgery42288113444

Pattern of Symptom Burden During Therapy

With regard to assessment compliance, the average MDASI-HN completion rate was 97% in weeks 1 to 2, 96% in weeks 3 to 4, and 87% in weeks 5 to 6. The mean MDASI-HN item ratings by treatment period and treatment group are depicted in Figure 1 and Table 2. Overall, the symptom rank order, in terms of symptom severity, shifted during the treatment course; the 10 symptoms rated as most severe (in order of decreasing mean severity) during weeks 1 to 2 of therapy were fatigue, dry mouth, drowsiness, problem tasting food, lack of appetite, disturbed sleep, distress, problem with mouth/throat mucus, pain, and problem swallowing/chewing; for weeks 6 to 7, the order was problem tasting food, problem with mouth/throat mucus, difficulty swallowing/chewing, fatigue, dry mouth, lack of appetite, mouth/throat sores, pain, skin pain/burning/rash, and drowsiness.

Figure 1.

Mean severity of the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module individual symptom items and overall symptom interference is shown across the treatment period according to treatment group. Mean individual symptom severity differences for the treatment groups (chemoradiotherapy vs radiotherapy) for the total sample period were compared using independent Student t tests. P values are shown (group differences were considered statistically significant if P < .002 for the 22 symptom items). DIST SLEEP indicates sleep disturbance; SHRT BREATH, shortness of breath.

Table 2. Mean University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module Item Ratings During RT or CCRT for Head and Neck Cancer by RT Period
 Week 0Weeks 1 to 2Weeks 3 to 5Weeks 6 to 7Total Sample
CCRTRTCCRTRTCCRTRTCCRTRTCCRTRTPa
MeanSDMeanSDMeanSDMeanSDMeanSDMeanSDMeanSDMeanSDMeanSDMeanSD
  1. Abbreviations: CCRT, concurrent chemoradiotherapy; RT, radiotherapy; SD, standard deviation.

  2. a

    Mean University of Texas MD Anderson Symptom Inventory-Head and Neck Module item severity differences for the treatment groups (CCRT vs RT) for the total sample period were compared using independent Student t tests with Bonferronni correction (group differences were considered significant if P <.002 for the 22 symptom items and P <.008 for the 6 interference items).

Core items
 Fatigue2.142.641.622.143.482.412.031.954.512.503.562.415.662.444.182.694.062.122.881.90.001
 Distress1.742.211.421.912.162.411.452.142.512.471.932.343.302.781.822.392.432.081.671.90.03
 Sleep disturbance1.882.781.432.072.532.431.471.853.362.462.552.374.072.753.023.093.022.122.101.84.01
 Sadness1.221.951.292.051.351.991.082.032.152.421.441.902.612.911.542.021.862.031.301.75.08
 Pain1.612.570.871.702.062.211.311.813.992.313.692.664.772.623.872.653.221.862.561.98.051
 Drowsiness1.502.410.911.512.842.541.431.523.572.402.832.514.552.902.752.773.202.152.081.80.001
 Numbness/tingling1.212.170.701.241.172.040.741.311.171.840.901.491.011.920.901.561.161.690.841.20.18
 Problem remembering1.071.770.751.401.492.060.721.351.521.961.151.801.942.371.131.941.511.830.931.42.04
 Lack of appetite1.042.050.801.872.752.681.392.014.852.753.352.655.023.304.203.273.722.122.462.08.001
 Dry mouth0.831.790.621.612.672.142.202.225.162.484.062.725.552.963.832.843.871.912.962.15.02
 Shortness of breath0.821.620.511.401.001.590.671.510.931.380.871.501.121.570.751.650.961.270.731.37.27
 Nausea0.581.480.421.282.032.501.041.602.802.432.172.123.422.832.172.542.341.961.521.51.01
 Vomiting0.030.240.050.360.801.830.281.211.802.240.921.492.122.671.452.501.311.530.661.10.003
Head and neck items
 Difficulty swallowing/chewing1.712.591.252.301.832.151.362.125.052.454.012.975.983.054.343.303.771.892.822.31.012
 Problem with mucus in mouth/throat1.252.220.922.002.002.291.461.694.942.493.512.676.312.714.153.283.801.842.531.96<.001
 Difficulty with voice/speech1.001.801.162.081.312.001.011.672.652.462.302.633.402.852.742.872.151.931.772.01.27
 Problem tasting food0.932.040.751.632.802.371.511.966.102.804.623.146.993.145.203.464.532.093.222.28.001
 Mouth/throat sores0.932.110.641.721.502.051.031.584.462.833.262.995.242.943.693.533.251.832.192.14.003
 Choking0.761.920.752.010.941.760.841.852.042.132.012.403.132.892.812.911.721.671.531.95.59
 Constipation0.611.340.551.191.422.180.781.572.262.261.501.742.632.551.942.251.881.761.171.34.01
 Problem with teeth/gums0.541.580.491.420.751.630.500.971.982.061.431.892.312.391.862.701.481.351.111.37.14
 Skin pain/burning/rash0.250.900.281.050.921.380.550.902.461.962.402.024.452.983.652.892.031.341.681.35.19
Symptom interference
 Enjoyment of life2.252.931.261.922.802.491.352.013.892.772.412.474.343.022.452.643.412.281.911.98<.001
 Normal work2.283.241.252.232.942.901.261.914.083.062.332.464.883.463.092.983.632.621.931.95<.001
 Mood1.882.471.391.971.922.041.261.932.982.592.092.323.722.892.392.542.632.141.751.90.009
 General activity2.183.131.091.782.932.391.181.803.922.802.652.565.162.973.002.923.592.302.021.94<.0.001
 Walking ability1.332.571.222.581.812.260.931.632.622.591.582.163.562.951.482.202.372.181.331.72.002
 Relations with other people1.392.420.751.431.522.120.941.992.292.421.572.153.332.761.742.422.102.021.271.83.008

Mean weekly severity scores for all 22 symptom items were 0.9 for baseline (pretreatment), 1.2 for week 1, 1.7 for week 2, 2.5 for week 3, 2.8 for week 4, 3.2 for week 5, and 3.4 for week 6 or 7; the corresponding mean weekly overall symptom interference scores were 1.5 (baseline), 1.5, 1.8, 2.4, 2.8, 2.9, and 3.4, respectively. Mixed model results demonstrated that overall symptom severity (P < .001) and symptom interference (P < .001) both became progressively worse over the course of treatment. The percentages of patients experiencing moderate to severe levels and severe levels of the 13 most prominent symptoms in each treatment period are shown in Figure 2.

Figure 2.

Percentages of patients experiencing (Top) moderate to severe levels (ratings of ≥ 5) or (Bottom) severe levels (ratings of ≥ 7) of the 13 most commonly experienced symptoms of the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module are shown according to treatment period.

Results from symptom cluster analyses at the end of treatment are shown in Figure 3. The majority of the top symptoms clustered into 1 of 2 distinct symptom groups: the local symptom cluster (eg, dry mouth, problem with mouth/throat mucus, difficulty chewing/swallowing, mouth/throat sores, and problem tasting food) and systemic symptom cluster (eg, pain, fatigue, drowsiness, and lack of appetite).

Figure 3.

Dendrogram illustrating the clustering of various symptoms at the end of treatment is shown. Those items that join with others earlier along the relative distance scale of 0 to 25 (ie, further to the left in this figure) were rated by patients more similarly. For example, the items Pain, Fatigue, and Drowsiness joined together quickly, indicating that patients perceived and rated these items similarly.

With regard to differences by treatment group, the overall mean symptom severity was worse for those receiving CCRT than for those receiving RT alone (2.9 vs 1.8; P < .001) (Fig. 4). The trajectories and comparisons for individual mean symptoms and overall symptom interference over the course of treatment are shown in Figure 1. The 5 symptoms that were found to be significantly more severe for those receiving CCRT compared with those receiving RT were fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food (Fig. 1). Overall mean symptom interference was higher for the CCRT group than for the RT group (2.5 vs 2.0; P < .006).

Figure 4.

Mean overall symptom severity of the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module symptom items across the treatment period is shown according to treatment group. 95% CI indicates 95% confidence interval.

Correlates of Symptom Severity

On univariate analysis, mixed model results demonstrated that receipt of CCRT (P < .006), T classification (P < .03), and ECOG performance status (P < .001) were significant correlates of symptom severity over time, whereas sex (P < .37), age (P < .47), primary tumor site (P < .09), previous treatment (P < .23), N classification (P < .77), and RT technique (P < .60) were not. On multivariate analysis, ECOG performance status and CCRT were the only significant correlates of symptom severity; higher mean symptom scores were reported for patients with poorer ECOG performance status (2.4 vs 2.1; P < .001) and those receiving CCRT rather than RT (2.5 vs 2.1; P < .04). Although symptom severity and group differences by T classification were similar in magnitude (2.4 vs 2.1; P < .20), the difference was not found to be statistically significant on multivariate analysis.

DISCUSSION

The current prospective longitudinal study uses a validated PRO instrument (MDASI-HN) to identify specific symptoms and their trajectory during RT, with or without concurrent chemotherapy, for patients with head and neck cancer. The majority of patients report relatively low tumor-associated symptom distress before treatment,[8] but the results of the current study indicate that for 7 of the 22 MDASI-HN individual symptom items, ≥ 50% of patients reported moderate to severe treatment-associated distress at some time during the treatment course (Fig. 2, Top). The specific time of symptom onset and their trajectories inform us about the required optimal timing for specific symptom interventions and patient education and preparedness. Unfortunately, reliable, effective, and validated specific interventions for many of these symptoms are not yet available. Nevertheless, the results of the current study provide benchmark data for power and sample size estimates for future clinical trials involving symptom interventions.

Although we have previously modeled patient group-based symptom severity differences and trajectories,[9] the current study further builds on those results in that it details the kinetic profile, including the relative emergence and incremental increase in magnitude, for individual local and systemic symptoms and symptom interference, and identifies unique symptoms clusters during RT for head and neck cancer. The most prominent local symptoms clustered: dry mouth, problem with mouth/throat mucus, mouth/throat sores, and difficulty chewing/swallowing. Systemic or global symptoms also formed distinct clusters, and the most prominent of these were fatigue, distress, disturbed sleep, and drowsiness. Relationally, these systemic symptom clusters may be attributed to local cytokine release and the systemic and inflammatory effects of cancer therapy,[12] as previously demonstrated in other disease sites,[13, 14] which may serve as target for future symptom prevention and intervention studies.

With regard to the impact of treatment group on symptom burden, chemotherapy concurrent with RT was found to significantly increase symptom severity. Although this was expected and well known in global terms,[12] we believe the results of the current study provide granular detail. It is interesting to note for example that although mouth and throat sores were substantially more severe in the CCRT group, the pain curves for RT and CCRT tracked relatively more closely. The greatest differences in symptom severity between those receiving CCRT versus those treated with RT (Fig. 3) were first observed early in the treatment course (weeks 1 and 2) and then again, and much more pronounced, toward the end of treatment (weeks 5 and 6), whereas symptom severity overlapped between the 2 groups in the middle of therapy (weeks 3 and 4). Furthermore, CCRT was associated with significantly increased overall symptom interference and specific interference subscales, and it significantly influenced both the severity and rank order of a subset of both local and systemic individual symptoms (ie, fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food). We are currently performing studies to evaluate the drivers of interference.

Beyond statistical comparisons, the shapes and trajectories of the overall symptom severity and individual symptom curves help to illustrate symptom differentials between treatment groups. For some symptoms, such as problem with taste, mouth/throat sores, and fatigue, the overall shape of the curves between treatment groups was quite similar, but the curves maintained separation with a higher severity of symptoms associated with CCRT. Others, such as dry mouth and problem with mouth/throat mucus, initially tracked and then diverged in the middle of treatment, whereas symptoms such as difficulty with voice/speech, skin pain/burning/rash, and choking tracked closely without separation. Despite these differing patterns in symptom variation between the RT and CCRT groups, the shape and trajectory of the corresponding interference curves separated at the onset, and remained so throughout treatment.

In terms of the clinical application of the MDASI-HN and the results of the current study, we believe that weekly sampling, although subject to potential concerns associated with response shift,[15] nonetheless promotes improved treatment compliance and reveals the progressive nature of individual acute symptoms in a manner that allows both prophylactic and reactive interventions to be timed effectively, in a way that maximizes clinic staff allocation (eg, opportunity for treatment group-specific and/or algorithm-based patient care pathways) and allows patients and caregivers to be given reliable information on the pattern of symptoms to be expected. For example, certain symptoms such as dry mouth, decreased appetite, and problem tasting food appeared early and steadily rose in severity across the treatment course, and as such these symptoms might be emphasized before therapy is begun. Conversely, other common symptoms such as mouth and throat sores and problems swallowing/chewing appeared more abruptly near the midpoint of therapy, with a subsequent rapid rise followed by a relative plateau in severity toward the end of the study period. Although patients are also informed of these before treatment, they may benefit from reemphasis in the middle of treatment. The increase in problems with choking in both groups underscores the importance of clinical swallowing evaluations, swallowing exercises, and maneuvers by speech language pathologists experienced in swallowing therapy, particularly for patients receiving CCRT. Beyond its role as a PRO instrument in multiple ongoing clinical protocols, we are currently using the MDASI-HN as part of our routine patient evaluation and as a management tool before, during, and after therapy.

Although these data were prospectively collected, the sampling limitations inherent in a single-institution series (in this case, a tertiary care specialty hospital) may affect the generalizability of the results. However, the population in the current study did reflect recent epidemiologic trends in head and neck cancer in that the majority of the patients were aged < 60 years, male, and had primary oropharyngeal cancer. Notably, one would expect many of the tested variables to be correlated with each other. For example, as is true in our recent practice patterns, the majority of patients with advanced lymph node disease received induction chemotherapy, most patients with oropharyngeal disease were treated with CCRT (Table 1), and nearly all patients were treated with IMRT rather than 3-dimensional conformal RT and standard fractionation radiation schedules were most commonly used. Furthermore, because we excluded patients who were being treated with palliative intent, the majority of the patients in the current study had good ECOG performance status before therapy began. Addressing these limitations will require additional longitudinal studies incorporating additional clinical variables (such as tumor human papillomavirus status, dosimetric details of RT, treatment compliance, and objective functional measures) to identify symptom kinetics across a wider array of patients with head and neck cancer, treatment modalities, management paradigms, and practice settings.

To our knowledge, the current series represents the first report of an individual symptom trajectory with symptom interference and cluster analyses based on a validated symptom burden PRO measure, and with high temporal granularity. Many of the studied symptoms do not have current effective, reliable, or validated specific prevention or direct treatment options. Consequently, on the basis of these results, we are conducting multiple prospective randomized clinical trials evaluating pharmacologic interventions that target purported candidate symptom mechanisms and expression pathways. We are also conducting additional longitudinal analyses to detail the symptom burden after the completion of RT or CCRT so that we can evaluate the influence of these acute symptoms on subsequent late symptom trajectory, recovery, and persistence into long-term survivorship. Additional robust symptom-related data are also necessary for statistical assumptions in future head and neck cancer trials in which symptom distress is an endpoint. This is particularly relevant because recent investigational treatment strategies undertaken by clinical trial cooperative groups have focused on treatment “deintensification” for selected patients (namely those with human papillomavirus-associated oropharyngeal cancer), with the goals of maintaining or improving established cure rates but reducing treatment-related toxicity and patient symptoms through the added evaluation of transoral robotic surgery (ECOG Trial 3311 [ClinicalTrials.gov identifier: NCT01898494]) and comparison of concurrent systemic therapy agents used in definitive chemoradiation strategies (Radiation Therapy Oncology Group Trial 1016 [ClinicalTrials.gov identifier: NCT01302834]).

The majority of patients in the current study experienced high symptom severity and symptom burden with a combination of problematic local and systemic symptom constellations. The pattern of symptoms and the degree of symptom interference was temporally distinct, being marked by an increased magnitude and a shift in individual symptom severity rank order over time, and with identifiable clusters of symptom subsets (both local and systemic). These findings will facilitate the rational development of symptom and specifically symptom cluster-based interventions and prevention strategies and help direct the importance of their relative timing. They further provide a reference data set for study design and statistical assumptions to be used in ongoing prospective clinical trials involving symptom intervention or reduction. Because to the best of our knowledge few reliable interventions have been identified for many of the most problematic local and systemic symptoms to date, additional research investigating symptom development or expression mechanisms and accompanying targeted symptom reduction strategies are urgently needed.

FUNDING SUPPORT

Supported in part by CA026582 from the National Cancer Institute to Charles Cleeland, PhD and by Cancer Center Support (CORE) grant CA016672 to The University of Texas MD Anderson Cancer Center.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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