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Impact of post-chemoradiotherapy superselective/selective neck dissection on patient reported quality of life
Oral Oncology, Volume 58, July 2016, Pages 21-26
- Neck dissection (ND) extent varies after CRT for head and neck cancer.
- We report QoL in pts who had superselective/selective ND after deintensified CRT.
- We saw acute but not long-term decrease in ND Impairment Index (functional) score.
- Limited post-CRT ND did not prevent recovery of most QoL metrics back to baseline.
- These data complement efficacy data for use of limited post-CRT NDs when indicated.
To describe patient-reported quality of life (QoL) for patients with HPV/p16-positive oropharyngeal squamous cell carcinoma undergoing post-chemoradiation (CRT) superselective or selective neck dissection (ND) as part of a prospective de-intensification study.
Materials and methods
Patients received 60 Gy IMRT with concurrent weekly cisplatin (30 mg/m2), followed by preplanned neck dissection of only originally involved nodal levels. QoL measures were assessed using the EORTC QLQ-C30 (general), EORTC H&N-35 (head and neck specific), EAT-10 (swallowing), and NDII (Neck Dissection Impairment Index) questionnaires. Early and late post-ND time points were compared to baseline and post-CRT/pre-ND time points.
37 patients underwent post-CRT superselective or selective ND. Median # of levels and nodes dissected were 2 and 12, respectively. EORTC QLQ-C30, H&N-35, and EAT-10 QoL scores worsened after CRT but continued to improve thereafter despite post-CRT ND. NDII score worsened initially after ND at the early post-ND time point (p = 0.023) but had recovered by the late post-ND time point (p = 0.672). Initial decrease in NDII was greater with ⩾12 nodes dissected (p = 0.007) and was correlated with the total number of nodes dissected (Spearman p = 0.027).
Use of post-CRT superselective and selective ND did not prevent recovery of most QoL metrics to near baseline. There was early but not late decrement in neck dissection specific QoL (NDII), more pronounced with more nodes dissected.
Abbreviations: QoL - quality of life, CRT - chemoradiation, ND - neck dissection, NDII - Neck Dissection Impairment Index.
Keywords: Oropharynx cancer, Squamous cell carcinoma, Chemoradiation, Selective, Superselective, Neck dissection, Quality of life, De-intensification, HPV.
Planned neck dissection (ND) was the historical standard of care after definitive radiation for head and neck cancer due to moderate rates of residual nodal disease in patients with positive nodes at diagnosis  and . However, routine post-radiation neck dissection may subject patients with pathologic complete response in the neck to the morbidity of surgery without any added benefit. During the 1990s, concurrent chemotherapy with radiation was shown to significantly improve outcomes, ushering a paradigm shift with increased usage of nonoperative definitive chemoradiation (CRT), especially in the setting of oropharyngeal and laryngeal cancer . In addition, there has been an increasing prevalence of HPV-associated oropharyngeal cancer, which carries a better prognosis and response to treatment .
There have also been many recent improvements in imaging techniques used to evaluate response to chemoradiation. Post-treatment CT and PET/CT are increasingly used to decide whether patients need a post-treatment neck dissection. In the setting of more effective treatments incorporating concurrent chemotherapy and more favorable tumor biology (i.e. HPV-association), numerous studies have shown that patients with a radiographic complete response in the neck may be spared the morbidity of surgery with a low risk of recurrence , , , , , and . Planned neck dissections have therefore declined in favor of an image-guided approach. A standard practice now is to obtain a PET/CT scan at 3 months post-treatment, reserving neck dissection for patients with evidence of residual disease.
The clinician-reported morbidity of a neck dissection has been previously documented in patients undergoing definitive surgery for head and neck cancer, with greater extent of dissection associated with greater morbidity , , , and , and further QoL decrements in patients with prior radiation , , , and . In a pooled analysis of several Radiation Therapy Oncology Group studies, post-CRT neck dissection was a significant predictor of grade 3 or higher late toxicity . However, the extent of neck dissections performed after radiation is evolving from the use of modified radical to selective and superselective (removal of 1–2 neck levels – i.e. only those initially harboring disease) dissections . There is increasing evidence that post-CRT superselective and selective neck dissections are safe and efficacious , , , , and . The impact of these limited post-CRT neck dissections on patient reported QoL is unknown, but may be useful to clinicians considering how to manage possible residual nodal disease after definitive chemoradiation.
We conducted a Phase II trial in which patients with HPV/p16-positive squamous cell carcinoma of the oropharynx received de-intensified chemoradiotherapy, followed by a superselective/selective neck dissection directed at pre-treatment positive lymph node levels. We collected a robust battery of patient reported QoL outcomes before CRT, before neck dissection, and at several time points after neck dissection. The purpose of this manuscript is to investigate the impact of superselective/selective neck dissection on changes in patient reported QoL after prior definitive chemoradiation.
Materials and methods
Study design and eligibility
This was a multi-institutional Phase II study examining de-intensified CRT. Full details can be found in our recent report . Informed consent was obtained from all patients. Inclusion criteria were as follows: Patients with untreated T0-3, N0-2c, M0 HPV and/or p16 positive squamous cell carcinoma of the oropharynx/unknown primary, ⩽10 pack-years smoking or >5 years abstinence from smoking, ⩾18 years of age, ECOG performance status 0–1, absolute neutrophil count ⩾1800 cells/mm3, platelet count ⩾100,000 cells/mm3, hemoglobin ⩾8.0 g/dl, serum creatinine <2.0 mg/dl, and negative pregnancy test in women of childbearing potential. Exclusion criteria were as follows: Prior history of head and neck cancer or head and neck radiation, pre-existing grade 2 neuropathy or hearing loss, known HIV-positive, and recent (within 6 months) severe comorbidity including unstable angina, congestive heart failure exacerbation, myocardial infarction, and/or COPD exacerbation.
Study treatment and planned surgical evaluation
Study treatment consisted of de-intensified CRT followed by biopsy of the primary site and limited neck dissection. The planned post-treatment surgery was chosen to provide a robust pathologic endpoint as well as to ensure safety in patients receiving both de-intensified radiation and de-intensified chemotherapy. All patients were treated with intensity modulated radiation therapy to 60 Gy (2 Gy per fraction) to areas of gross disease and 54 Gy (1.8 Gy per fraction) to regions considered at risk for subclinical disease. Radiation was delivered over six weeks, five days a week. Chemotherapy consisted of concurrent weekly cisplatinum, 30 mg/m2 for a total of six weekly doses. At 4–8 weeks post-CRT, patients received a response assessment including physical exam, fiberoptic nasolaryngopharyngoscopy, and diagnostic CT. Within 6–14 weeks after CRT, patients underwent the planned surgical evaluation. Patients with a complete clinical response at the primary site underwent a biopsy, followed by transoral surgery only if residual disease was present. All patients with initially node-positive disease received a superselective or selective neck dissection, defined as the removal of at least all previously involved nodal levels. Patients found to have residual nodal disease did not undergo any further neck surgery. Starting one month after surgery, all patients received massage therapy.
Quality of life assessment
Four validated questionnaires were used to assess patient-reported quality of life: the EORTC QLQ-C30 assessment of general QoL, the EORTC H&N-35 assessment of head and neck specific QoL, the EAT-10 assessment of swallowing, and the NDII (Neck Dissection Impairment Index) assessment of neck dissection-specific QoL. These are discussed in further detail below. The study schema is shown in Fig. 1. The QLQ-C30, H&N-35, and EAT-10 were collected pre-CRT, 6 weeks post-CRT (pre-neck dissection), and post-neck dissection at each subsequent follow-up visit. The NDII was collected at 6 weeks post-CRT (pre-ND) and at subsequent post-ND follow-up visits, but not pre-CRT. For the purposes of this study, we defined four distinct time points: Pre-CRT (Baseline), Pre-ND (Post-CRT), Early Post-ND (First QoL assessment after neck dissection) and Late Post-ND (Closest QoL assessment to 1.5 years post neck dissection). To assess the specific impact of the neck dissection, we compared the Pre-ND (Post-CRT) time point with the Early and Late Post-ND time points.
- 1. EORTC QLQ-C30 : The EORTC QLQ-C30 is a core questionnaire that is a reliable and valid measure of the quality of life of cancer patients. It incorporates nine multi-item scales: five function scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and an overall global QoL scale. Several single-item symptom measures are also included. Higher numbers represent better QoL for the global and function scales, but worse QoL for the symptom scales and items.
- 2. EORTC H&N-35 : The EORTC QLQ H&N-35 is a validated questionnaire designed to assess the quality of life of head and neck cancer patients in conjunction with the general cancer-specific EORTC QLQC-30. The H&N-35 incorporates additional single-item symptom measures of particular relevance, i.e. mouth opening, dental health, speech, dry mouth, etc. Higher raw scores represent worse QoL.
- 3. EAT-10 : The EAT-10 is a validated self-administered instrument for documenting dysphagia severity. This questionnaire uses symptom-specific scores to assess dysphagia with solids, liquids, and pills as well as the impact of dysphagia on mental, social and physical health. Higher raw scores represent worse QoL.
- 4. NDII : The Neck Dissection Impairment Index (NDII) is a validated instrument designed to assess the specific impact of neck dissections on quality of life. Items on this questionnaire measure the degree of neck/shoulder pain and stiffness, limitations imposed on patient physical function, and the impact of these limitations on activity. Higher raw scores represent better QoL.
The endpoints of this study were the temporal changes in QoL scores for the four questionnaires presented above. Composite and itemized QoL scores were compared between different time points using a two-tailed paired sample t-test. An independent sample t-test was used to compare the degree of change in QoL score for various ordinal clinical parameters (such as number of nodes dissected) using the median as a cutpoint. Spearman correlation coefficient was used to assess linear correlation between QoL score changes and clinical parameters.
Clinical characteristics are summarized in Table 1. All 44 accrued patients received the intended radiation dose of 60 Gy and 93% received four or more of the six planned weekly doses of cisplatin. We excluded one patient who had an incomplete response at the primary site requiring a transoral surgery and all patients who did not have a neck dissection (patients who were node-negative), leaving 37 evaluable patients. Complete clinical and pathologic outcomes were presented in our recent publication .
|Characteristics||n = 37|
|Median age (range)||61 yrs (44–77 yrs)|
|Primary tumor site|
|Base of tongue||20 (54%)|
|Unilateral vs bilateral neck radiation|
|Unilateral vs bilateral neck dissection|
|Number of neck levels dissected (including both necks)|
|One level||13 (35%)|
|Two levels||14 (38%)|
|Three levels||5 (13%)|
|Four levels||1 (3%)|
|Five levels||3 (8%)|
|Six levels||1 (3%)|
|Number of nodes dissected (including both necks)|
|19 or more||10 (27%)|
Surgical evaluation including biopsy of the primary site and neck dissection was performed a median nine weeks after completion of CRT. Median number of neck levels dissected was 2 (range, 1–6). 73% of patients had a superselective ND (1 or 2 lymph node levels dissected) and the remainder had a selective ND. Five patients had a bilateral ND. The most commonly dissected neck level was level II (95% of patients), followed by level III (65%) and level IV (24%). Levels I and V were rarely dissected (5% of patients). Median number of nodes dissected was 12 (range, 1–46).
Quality of life – EORTC QLQ-C30, EORTC H&N-35, and EAT-10
Complete quality of life outcomes for the EORTC QLQ-C30, EORTC H&N-35, and EAT-10 assessments are shown in the Appendix (Supplementary Table 1). 37 patients (36 for the EAT-10) completed Baseline, Pre-ND, and Early Post-ND assessments, and 31 patients (29 for the EAT-10) completed the Late Post-ND assessment. Median interval between neck dissection and Early and Late Post-ND time points was 2 months (range, 1–7) and 16 months (range, 10–21), respectively. Fig. 2 summarizes QoL scores for study assessments at the four time points (for this figure, all metrics’ overall scores were scaled to 100 with higher numbers representing better QoL for ease of comparison). Overall QLQ-C30, H&N-35, and EAT-10 scores decreased after CRT. QoL scores improved over time after superselective/selective neck dissection, and composite EORTC QLQ-C30, H&N-35, and EAT-10 recovered almost to baseline values. There was no association between extent of neck dissection (i.e. number of nodes dissected, number of neck levels dissected, bilateral vs. unilateral neck dissection) and change in QoL score. Neither was there an association between extent of radiation (bilateral vs. unilateral) and change in QLQ-C30 or H&N-35 score. Patients who received unilateral neck radiation had better improvement in EAT-10 scores (Pre-ND vs. Early Post-ND [n = 7, p = 0.079] and Pre-ND vs. Late Post-ND [n = 5, p = 0.02]) compared to patients who received bilateral neck radiation.
Quality of life – Neck Dissection Impairment Index (NDII)
Quality of life outcomes for the NDII are shown in Table 2. For the NDII, 31 patients completed Pre-ND and Early Post-ND assessments, and 30 patients completed the Late Post-ND assessment (there was no Baseline/Pre-CRT assessment of the NDII). Median interval between neck dissection and Early and Late Post-ND time points was 1.4 months (range, 1–3.5) and 18 months (range, 10–37), respectively. Unlike the other QoL assessments, there was a significant worsening of the overall NDII score from Pre-ND to the Early Post-ND time point (87.4 vs. 80.2, p = 0.023) but not the Late Post-ND time point (87.4 vs. 88.0, p = 0.672), as shown in Fig. 2. Many individual items were significantly worse at the Early Post-ND time point. However, the only individual items that were significantly worse at the Late Post-ND time point were pain/discomfort (p = 0.032) and reaching above (p = 0.03). There was an association between number of neck nodes dissected and worsening NDII score (Fig. 3). Patients who had fewer than 12 nodes dissected did not report decrement in QoL (as measured by NDII) after superselective/selective neck dissection, whereas patients with 12 or more nodes dissected reported a decrement at the Early Post-ND time point, and recovery to baseline at the Late Post-ND time point.
|Domain||Mean (SD)||p value|
|Pre-ND||Early Post-ND||Late Post-ND||Pre-ND vs. Early Post-ND||Pre-ND vs. Late Post-ND|
|(n completing surveys)||31||31||30|
|Overall NDII score||87.4 (12.3)||80.2 (20.5)||88.0 (13.8)||0.023||0.672|
|Pain/discomfort||4.5 (0.8)||3.8 (1.0)||4.0 (1.0)||0.001||0.032|
|Stiffness||4.6 (0.7)||3.7 (1.2)||4.2 (1.0)||<0.001||0.062|
|Self-care||4.9 (0.3)||4.5 (1.0)||4.8 (0.6)||0.021||0.326|
|Lifting light objects||4.6 (0.7)||4.3 (1.2)||4.4 (0.9)||0.059||0.522|
|Lifting heavy objects||4.3 (1.1)||3.6 (1.4)||4.2 (1.2)||0.004||1.000|
|Reaching above||4.7 (0.7)||4.0 (1.3)||4.4 (0.8)||<0.001||0.030|
|Overall activity||4.3 (0.8)||4.0 (1.1)||4.4 (0.9)||0.125||0.763|
|Social activity||3.8 (1.2)||4.1 (1.2)||4.6 (0.8)||0.097||0.001|
|Leisure/recreation||4.0 (1.1)||4.1 (1.2)||4.4 (0.9)||0.778||0.074|
|Ability to work||4.0 (1.1)||3.9 (1.2)||4.5 (1.0)||0.687||0.066|
Abbreviations: SD, standard deviation; ND, neck dissection. Note: The Overall NDII score is shown bolded and is calculated by summing individual NDII item scores and converting to a scale of 0–100. Higher numbers represent better quality of life.
Fig. 4A shows the acute change in NDII score from Pre-ND to Early Post-ND and Fig. 4B shows the long term change from Pre-ND to Late Post-ND by individual items and number of nodes dissected. The acute decrease in the overall NDII was greater in patients with 12 or more nodes dissected (p = 0.007) and was correlated with the total number of nodes dissected (Spearman p = 0.027). When considering individual items, patients with 12 or more nodes dissected had significantly greater acute QoL decreases in pain/discomfort (p = 0.004), stiffness (p = 0.006), self-care (p = 0.045), lifting light objects (p = 0.017), lifting heavy objects (p = 0.013), reaching above (p = 0.009), and overall activity level (p = 0.028), but not socialization (p = 0.957), leisure/recreation (p = 0.086), and ability to work (p = 0.142) as compared to patients with fewer than 12 nodes dissected. At the Late Post-ND time point, there was no longer a significant difference based on number of nodes dissected for the overall NDII score (p = 0.319) or for any individual item. There was no association between number of neck levels dissected, bilateral ND, or bilateral neck radiation and change in NDII score.
In this study, we provide one of the first reports on the quality of life and neck function of patients who receive chemoradiation followed by a limited post-CRT neck dissection. Though there is wide variation in the approach to potential residual nodal disease after definitive chemoradiation, the use of superselective neck dissection directed at only pre-treatment positive lymph node levels is becoming more common. Our data may be useful for clinicians considering this approach. We assessed QoL in patients with favorable risk HPV/p16-positive OPSCC enrolled in a prospective phase II clinical trial of de-intensified chemoradiation followed by a preplanned post-CRT superselective/selective neck dissection. As expected, patients reported initial decrement in QoL after CRT with return to baseline approximately 1.5 years after completion of CRT. We observed further early decrement in QoL scores after neck dissection only with the one validated QoL instrument designed specifically for patients undergoing a neck dissection; however the decrement was mild and neck dissection-specific QoL returned to Pre-ND baseline levels. Patients who had fewer than 12 nodes dissected did not report reduction in neck dissection-specific QoL at either Post-ND time point.
For the general QLQ-C30, head and neck specific H&N-35, and swallowing specific EAT-10 metrics, the continued improvement in QoL from the Pre-ND to the Early Post-ND time point suggests that the addition of a post-CRT neck dissection did not prevent recovery of QoL after CRT, though we are unable to ascertain if the neck dissection slowed recovery. The superselective/selective neck dissection did not seem to prolong feeding tube use (41% required feeding tube Pre-ND vs. 16% Early Post-ND and 0% Late Post-ND). In contrast, the Neck Dissection Impairment Index, designed to assess the specific functional impact of a neck dissection, did show a decline in QoL from the Pre-ND time point to the Early Post-ND time point. However, patients did eventually recover to Pre-ND levels with long-term follow-up. The change in QoL shortly after neck dissection is summarized by Supplementary Table 2 (Appendix), which separates itemized QoL metrics into those that worsened, were stable, or improved between the Pre-ND and Early Post-ND time points.
Several studies have demonstrated that the use of selective neck dissection omitting one or more lymph node levels after radiation is safe with low recurrence rates  and . Other studies suggest further limiting post-CRT neck dissections to removal of only pre-treatment positive nodal levels. In an analysis by Robbins et al. examining pathologic results in patients undergoing early post-CRT salvage neck dissection of at least three nodal levels, a superselective dissection with removal of only the initially involved level would have encompassed all pathologic disease in 52 of 54 patients . Furthermore, Yeung et al. reported that in a cohort of 274 patients undergoing post-CRT neck dissection, 623 out of 640 neck levels that were CT-negative after radiation harbored no pathologic disease. This corresponded to a negative predictive value of 97%, arguing for further limitation of the post-treatment neck dissection to perhaps only levels of residual adenopathy . It is important to note that these limited dissections should only be performed in the setting of a preplanned evaluation (as in our trial) or as early salvage for residual disease detected on an initial post-treatment scan. The QoL here-in presented in our study complements these aforementioned studies, which provide support for the use of superselective/selective ND when indicated by post-CRT imaging.
Our results also showed that the number of lymph nodes dissected may be an important factor for the one instrument (NDII) that did suggest that neck dissection had an effect on QoL. Patients with 12 or more nodes dissected accounted for the acute QoL decline seen in most of the NDII items between the Pre-ND and Early Post-ND time points. However, even these patients had recovered to almost Pre-ND function by the Late Post-ND time point. These findings are consistent with previously published trials that examined the impact of differing extents of neck dissections  and . In contrast, Donatelli-Lassig et al. reported no differences in QoL other than increased pain in patients who had a post-CRT neck dissection as compared to patients who had CRT alone . However, that study did not include an assessment of functional outcomes (such as the Neck Dissection Impairment Index).
The importance of functional or specific assessments to capture surgical morbidities that may not be reflected in other QoL scores is illustrated by several studies. The best example comes from Schiefke et al., who compared sentinel lymph node biopsy vs. selective neck dissection. In that study, the sentinel lymph node group had better objective scores measuring scarring, lymphedema, sensory function, and shoulder function using the Constant Shoulder Score. However, that difference was not reflected in their QoL scores as assessed by the EORTC QLQ-C30 and H&N-35 . The inability of the QLQ-C30 and H&N-35 to detect these objective differences may reflect a broader limitation of their use in quality of life studies: though overall and average QoL scores may be good, clinically meaningful differences in specific realms are easily masked. Similarly, a study by Murer et al. also showed better functional outcomes after sentinel lymph node dissection vs. more extensive elective neck dissections when using the Neck Dissection Impairment Index and the Constant Shoulder Score . Though patients in our study had pre-ND chemoradiation and more advanced cancers, our results were similar in that we also detected a functional impact of limited neck dissections on NDII score and no apparent effect on other QoL metrics.
Our study has several limitations. One significant limitation is that we did not have Pre-CRT data available for the NDII questionnaire or a comparison group that did not receive neck dissections. In addition, there was variation in the time between surgery and questionnaire administration, especially for the Late Post-ND assessment. The protocol-specified biopsy of the primary site could possibly confound QoL scores at the Early Post-ND time point, but we would not expect a major impact on most QoL indices used. All patients received nonstandard de-intensified CRT in this trial, which may contribute to the favorable QoL outcomes observed. The sample size was small, making it difficult to assess the impact of specific variables across patients. Additionally, our study suffers from limitations common to most quality of life studies. First is the phenomenon of “response shift,” in which human adaptation leads to changes in patients’ expectations and perceptions of quality of life over the course of a longitudinal study . Second, though quality of life studies can often detect statistically significant differences in individual metrics, it is nebulous as to what defines a “clinically significant” difference, especially as this definition may vary among individuals.
In conclusion, our standard practice at UNC/UF is to perform a 3 month post-CRT PET/CT followed by observation if the results are negative. If the post-CRT PET/CT is positive, we perform a superselective neck dissection (limited to pre-CRT positive nodal levels). If the PET/CT is equivocal, we perform a repeat PET/CT scan at 6 months post-CRT in favorable risk patients (HPV-associated oropharyngeal primary), but proceed to superselective neck dissection in intermediate or high risk patients (HPV-negative or significant smoking history). Others have reported that limiting post-CRT neck dissection to removal of only the initially positive nodal levels is safe and efficacious, and the QoL data we report in this study further complement this approach. Superselective and selective neck dissections may not adversely affect long term recovery of QoL after CRT, especially in patients with fewer nodes dissected.
Role of the funding source
Funding was provided by the University of North Carolina School of Medicine, Department of Radiation Oncology and University of Florida School of Medicine, Department of Radiation Oncology.
Conflict of interest statement
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a Department of Radiation Oncology, University of North Carolina Hospitals, 101 Manning Drive, CB #7512, Chapel Hill, NC 27599-7512, USA
b Department of Radiation Oncology, Health Science Center, University of Florida Hospitals, PO Box 100385, Gainesville, FL 32610-0385, USA
c Department of Otolaryngology, Division of Head and Neck Surgery, University of North Carolina Hospitals, 170 Manning Drive, CB #7070, Chapel Hill, NC 27599-7070, USA
⁎ Corresponding author. Tel.: +1 984 974 0400 (Office); fax: +1 919 966 7681.
© 2016 Published by Elsevier B.V.