ABSTRACT
Objective
To investigate adjuvant therapy considerations, utilization, and associated overall survival (OS) following upfront laryngectomy for laryngeal squamous cell carcinoma (LSCC).
Methods
The 2010 to 2017 National Cancer Database was retrospectively reviewed for patients undergoing upfront laryngectomy (N = 3360). Kaplan–Meier, multivariable binary logistic, and Cox proportional hazards regression models were implemented.
Results
Among 2997 patients with consideration(s) for adjuvant radiotherapy (aRT) (i.e., pT3‐4, pN2‐3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and/or positive surgical margins [PSM]), 1176 (39.2%) did not undergo adjuvant therapy and were considered to have missed aRT. Among 992 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) (i.e., pENE and/or PSM), 169 (17.0%) underwent aRT alone and were considered to have missed aCRT. Older age and increased distance to the reporting facility were associated with higher adjusted odds of both missed aRT (p < 0.001) and missed aCRT (p < 0.025). Patients with pENE only (N = 343, 57.6%) and pENE and PSM (N = 96, 56.8%) underwent aCRT more frequently than those with PSM only (N = 97, 42.5%) (p < 0.001). Missed aRT was associated with worse OS among 2005 patients with consideration(s) for aRT alone (i.e., pT3‐4, pN2‐3 classification, and/or LVI without pENE or PSM) (aHR 1.23, 95% CI 1.05–1.44, p = 0.011) and among 992 patients with consideration(s) for aCRT (aHR 1.85, 95% CI 1.52–2.24, p < 0.001).
Conclusion
Missed aRT following upfront laryngectomy for LSCC occurs frequently and portends worse OS. Identifying patients at risk of off‐guideline management may create opportunities for quality improvement in the multidisciplinary care of patients undergoing upfront laryngectomy for LSCC.
Level of Evidence
4.
Keywords: adjuvant, laryngeal, missed, National Cancer Database, survival
1. Introduction
Laryngeal cancer is associated with lifelong morbidity because of treatment‐induced speech and swallowing dysfunction [1, 2, 3, 4]. The estimated incidence in 2022 was 12,470 patients, representing 19% of all head and neck cancers (HNCs), and just 1% of all cancers [5]. The estimated number of deaths in 2022 was 3,820; the risk of mortality therefore remains high [5].
In 1991, the Veterans Affairs Laryngeal Cancer Study Group demonstrated similar recurrence‐free survival between patients undergoing induction chemotherapy followed by either (1) definitive radiotherapy for those responding or (2) laryngectomy + adjuvant radiotherapy (aRT) for those not responding [1, 6, 7, 8]. Additional clinical trials such as Radiation Therapy Oncology Group (RTOG) 9111 supported these findings and the role of primary chemoradiotherapy in optimizing tumor eradication and quality of life [9, 10, 11]. In fact, between 1997 and 2008, the number of laryngectomies performed in the United States decreased by 48%, consistent with trends favoring laryngeal preservation [10, 12, 13, 14, 15, 16, 17]. Nevertheless, laryngectomy is typically indicated for advanced tumor presentations (i.e., cT4a) failing primary chemoradiotherapy (i.e., salvage laryngectomy), as these patients have poor laryngeal function and are unlikely to achieve remission without surgery [8, 13, 18, 19, 20, 21, 22, 23, 24, 25].
Patients with adverse features such as pT3‐4, pN2‐3 classification, pathologic extranodal extension (pENE), lymphovascular invasion (LVI), perineural invasion (PNI), and positive surgical margins (PSM) are recommended to undergo adjuvant therapy to improve locoregional control and survival [26, 27, 28, 29, 30, 31]. Traditionally, 40–70 Gy of external beam radiation is delivered in daily fractions for 5 days per week, for approximately 6 weeks, with a median cumulative dose of 60 Gy [32]. As many as 25% of patients with HNC are documented as missing aRT and having worse OS [26, 33, 34, 35, 36]. National practice patterns regarding adjuvant therapy for laryngeal squamous cell carcinoma (LSCC) are understudied, and identifying patients at risk of off‐guideline management may improve outcomes. Our study of the National Cancer Database (NCDB) investigates adjuvant therapy considerations, utilization, and associated survival disparities following upfront laryngectomy for LSCC.
2. Methods
2.1. Data Source
The NCDB is a collaborative initiative between the American Cancer Society and the Commission on Cancer (CoC) of the American College of Surgeons, compiling information from > 1500 CoC‐accredited hospitals across the United States and capturing > 70% of newly diagnosed cancer cases each year [37, 38] Given that the patient data are de‐identified, our study was deemed exempt by the Institutional Review Board at Rutgers New Jersey Medical School. The statistical analyses and interpretations presented are solely those of the authors and do not reflect the views of the ACS or the CoC.
2.2. Inclusion Criteria
The NCDB was retrospectively reviewed for adults diagnosed with LSCC between January 2010 and December 2017, undergoing upfront laryngectomy (i.e., subtotal [including partial, hemi‐, vertical, anterior commissure, or supraglottic], total [including radical or pharyngolaryngectomy], or unspecified) with curative intent (Figure 1). LSCC was identified using International Classification of Diseases for Oncology, Third Edition (ICD‐O‐3) histology (“8050‐8052,” “8070‐8078,” “8083,” and “8084”), behavior (“3”), and topography (“C32.0” for glottis; “C32.1” for supraglottis; “C32.2” for subglottis; “C32.3”, “C32.8”, and “C32.9” for other [laryngeal cartilage, overlapping, and unspecified, respectively]) codes. pTN classification was determined according to the guidelines outlined by the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th Edition.
FIGURE 1.
Inclusion criteria. aCRT, adjuvant chemoradiotherapy; aRT, adjuvant radiotherapy; cM, clinical metastasis; LSCC, laryngeal squamous cell carcinoma; NCDB, National Cancer Database; pTN, pathologic tumor‐nodal.
Patients were excluded if they had a diagnosis lacking histologic confirmation; a history of prior malignancy; unknown grade, pathologic tumor (pT), pathologic nodal (pN), clinical metastasis (cM) classification, pENE, LVI, surgical margins, adjuvant therapy, vital status, or survival time; staging not performed using the AJCC Cancer Staging Manual, 7th edition; carcinoma in situ; distant metastasis (cM1); treatment with palliative intent; treatment without neck dissection; aRT initiation > 90 days after laryngectomy; neoadjuvant radiotherapy or chemotherapy; salvage laryngectomy; sequential aCRT (i.e., chemotherapy not started within 28 days of aRT initiation); or adjuvant chemotherapy alone.
2.3. Variables
Patient data included age at diagnosis, sex, race, primary payer, reporting facility type, distance to the reporting facility, Charlson–Deyo comorbidity score (CDCS), history of prior malignancy, histology, primary site, grade, pTpNcM classification, pENE, LVI, neck dissection, surgical margins, adjuvant therapy, 30‐day unplanned readmission to the surgical facility following discharge, 30‐day mortality and 90‐day mortality following upfront laryngectomy, vital status, and survival time. A CDCS of 0 indicates no major recorded comorbid conditions. An academic/research facility is defined by the NCDB as an institution recording > 500 newly diagnosed cancer cases annually, participating in postgraduate medical education and cancer‐related research, and offering the full range of diagnostic and treatment services on‐site. Non‐academic/research facilities pool together community (records > 100 but < 500 newly diagnosed cancer patients annually), comprehensive community (records > 500 newly diagnosed cancer patients annually), and integrated network (no minimum caseload but owns, operates, leases, or is part of a joint venture offering comprehensive services) facilities. Tumor grade was grouped into low (well or moderately differentiated) and high (poorly differentiated, undifferentiated, or anaplastic). PSM included residual tumor, described as microscopic, macroscopic, or unspecified. Neck dissection was defined as the retrieval and examination of ≥ 10 lymph nodes, a threshold supported by prior HNC studies [33, 35, 39, 40, 41, 42, 43, 44, 45] aRT was defined as therapeutic doses (44–80 Gy) of external beam radiation to the head and neck, administered during the initial phase of radiotherapy and initiated within 90 days post‐surgery. aCRT was defined as any chemotherapy regimen—regardless of agent type or number—started within 28 days of beginning aRT. The primary endpoint was 5‐year overall survival (OS), calculated from the date of diagnosis to death or 5 years of follow‐up, whichever occurred first.
Considerations for aRT reported in the NCDB included pT3‐4, pN2‐3 classification, pENE, LVI, and PSM [26, 35, 46]. Patients with such indications who did not receive aRT or aCRT were considered to have missed aRT.
Considerations for adjuvant chemoradiotherapy (aCRT) were obtained from the European Organization for Research and Treatment of Cancer 22,931 and RTOG 9501 clinical trials, and included pENE and PSM [26, 27, 28, 29, 30, 46, 47]. Patients were considered to have missed aCRT if they had consideration(s) for aCRT but underwent aRT alone.
2.4. Statistical Analysis
Categorical variables were compared using the chi‐square test and Bonferroni correction. Continuous variables were tested for normality using the Shapiro–Wilk method and summarized with medians, interquartile ranges, and Kruskal‐Wallis H statistics. Proportional differences and associated 95% confidence intervals (CIs) for categorical variables were calculated using the normal distribution approximation without continuity correction. Mean differences and associated 95% CIs for continuous variables were calculated using the independent samples t‐test assuming unequal variance due to the significance of Levene's test. Patients with consideration(s) for aRT were categorized as having a stage consideration (i.e., pT3‐4 and/or pN2‐3 classification), pathologic consideration (i.e., LVI, pENE, and/or PSM), or both; patients with consideration(s) for aCRT were categorized as having pENE only, PSM only, or both. Kaplan–Meier survival curves were generated for 5‐year OS, and comparisons were made using the log‐rank test. Multivariable binary logistic and Cox regression models handling missing data with listwise elimination (i.e., complete‐case analysis) and adjusting for significant variables on univariable regression were implemented to identify associations with missed aRT, missed aCRT, and OS. The proportional hazards assumption was tested using time‐dependent covariates and was found not to be violated. To account for immortal time bias and patients with favorable baseline prognosis having a higher likelihood of undergoing definitive local therapy, landmark survival analysis was performed for patients surviving 6 from diagnosis [22]. A two‐sided p‐value of less than 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics version 25 and Microsoft Excel.
3. Results
3360 patients undergoing upfront laryngectomy for LSCC satisfied inclusion criteria (Figure 1). Median (interquartile range [IQR]) patient age was 60 (54–67) years (Table 1). A high proportion of patients were male (79.0%), White (80.7%), treated at academic/research reporting facilities (66.6%), and had supraglottic disease (43.5%) classified as low grade (72.2%), pT4 (54.1%), and pN0 (51.0%). The rate of pENE, LVI, and PSM was 22.7%, 31.8%, and 11.8%, respectively. Following upfront laryngectomy, 177 (5.5%) patients had unplanned readmission within 30 days, 48 (1.4%) had mortality within 30 days, and 105 (3.1%) had mortality within 90 days. Median (IQR) days from laryngectomy to aRT initiation was 51 (42–63). Median (IQR) aRT dose was 60 (60–66) Gy, and median (IQR) aRT duration was 45 (43–50) days.
TABLE 1.
Patient demographics and clinicopathologic features by adjuvant therapy indicated, n (%).
| Consideration(s) for aRT | Consideration(s) for aCRT | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| aRT alone or aCRT | Missed aRT (i.e., no adjuvant therapy) | p | Proportional difference (95% CI) | aCRT | Missed aCRT (i.e., aRT alone) | p | Proportional difference (95% CI) | Total | |
| No. | 1821 | 1176 | — | 536 | 169 | — | 3360 | ||
| Age at diagnosis, median years (IQR) | 59 (53–66) | 62 (55–70) | < 0.001 | −3.3 (−4.1 to −2.6) | 59 (53–65) | 61 (55–69) | 0.003 | −2.6 (−4.3 to −1.0) | 60 (54–67) |
| Sex | |||||||||
| Male | 1487 (81.7) | 926 (78.7) | 0.049 | 2.9 (−0.0–5.9) | 430 (80.2) | 124 (73.4) | 0.058 | 6.9 (−0.6–14.3) | 2654 (79.0) |
| Female | 334 (18.3) | 250 (21.3) | −2.9 (−5.9–0.0) | 106 (19.8) | 45 (26.6) | −6.9 (−14.3–0.6) | 706 (21.0) | ||
| Race | |||||||||
| White | 1429 (79.0) | 954 (82.1) | 0.099 | −3.2 (−6.0 to −0.3) | 422 (79.3) | 132 (78.1) | 0.602 | 0.6 (−6.5–7.8) | 2685 (80.7) |
| Black | 330 (18.2) | 183 (15.7) | 2.5 (−0.3–5.2) | 91 (17.1) | 33 (19.5) | −2.5 (−9.3–4.2) | 558 (16.8) | ||
| Other | 51 (2.8) | 25 (2.2) | 0.7 (−0.5–1.8) | 19 (3.6) | 4 (2.4) | 1.2 (−1.6–4.0) | 86 (2.6) | ||
| Primary payer status | |||||||||
| No insurance | 149 (8.4) | 78 (6.9) | < 0.001 | 1.5 (−0.3–3.4) | 42 (8.1) | 11 (6.9) | 0.239 | 1.3 (−3.0–5.7) | 244 (7.5) |
| Private insurance | 517 (29.3) | 253 (22.4) | 6.9 (3.7–10.0) | 157 (30.1) | 39 (24.4) | 6.2 (−1.2–13.6) | 920 (28.3) | ||
| Medicaid | 489 (27.7) | 259 (22.9) | 4.8 (1.7–8.0) | 142 (27.3) | 41 (25.6) | 2.2 (−5.2–9.7) | 803 (24.7) | ||
| Medicare | 611 (34.6) | 541 (47.8) | −12.5 (−16.0 to −8.9) | 180 (34.5) | 69 (43.1) | −7.2 (−15.7–1.2) | 1282 (39.5) | ||
| Reporting facility type | |||||||||
| Academic/research | 1120 (62.4) | 837 (72.0) | < 0.001 | −9.7 (−13.1 to −6.2) | 343 (65.0) | 102 (61.1) | 0.362 | 3.6 (−4.8–12.1) | 2207 (66.6) |
| Non‐academic/research | 674 (37.6) | 326 (28.0) | 9.3 (5.9–12.7) | 185 (35.0) | 65 (38.9) | −3.9 (−12.3–4.4) | 1107 (33.4) | ||
| Distance to reporting facility, median mi (IQR) | 16.8 (5.7–39.8) | 26.1 (8.9–60.6) | < 0.001 | −20.6 (−29.2 to −12.1) | 17.8 (5.3–41.4) | 17.3 (5.1–57.9) | 0.503 | −16.2 (−34.2 to −1.8) | 19.9 (6.9–47.8) |
| CDCS | |||||||||
| 0 | 1237 (67.9) | 780 (66.3) | 0.061 | 1.6 (−1.8–5.1) | 355 (66.2) | 101 (59.8) | 0.306 | 6.5 (−1.9–14.9) | 2243 (66.8) |
| 1 | 413 (22.7) | 254 (21.6) | 1.1 (−2.0–4.1) | 129 (24.1) | 49 (29.0) | −4.9 (−12.7–2.8) | 762 (22.7) | ||
| 2 | 171 (9.4) | 142 (12.1) | −2.7 (−5.0 to −0.4) | 52 (9.7) | 19 (11.2) | −1.5 (−6.9–3.8) | 355 (10.6) | ||
| Primary site | |||||||||
| Glottis | 533 (29.3) | 317 (27.0) | 0.128 | 2.3 (−1.0–5.6) | 110 (20.5) | 41 (24.3) | 0.670 | −3.7 (−11.0–3.6) | 937 (27.9) |
| Supraglottis | 753 (41.4) | 471 (40.1) | 1.3 (−2.3–4.9) | 272 (50.7) | 86 (50.9) | −0.1 (−8.8–8.5) | 1463 (43.5) | ||
| Subglottis | 56 (3.1) | 33 (2.8) | 0.4 (−0.6–1.4) | 12 (2.2) | 3 (1.8) | 0.7 (−1.8–3.1) | 95 (2.8) | ||
| Other | 479 (26.3) | 355 (30.2) | −3.9 (−7.6 to −0.2) | 142 (26.5) | 39 (23.1) | −1.6 (−8.0–4.8) | 865 (25.7) | ||
| Grade | |||||||||
| Low | 1271 (69.8) | 867 (73.7) | 0.020 | −3.9 (−7.0 to −0.9) | 328 (61.2) | 111 (65.7) | 0.294 | −4.5 (−11.0–2.0) | 2426 (72.2) |
| High | 550 (30.2) | 309 (26.3) | 3.9 (0.9–6.9) | 208 (38.8) | 58 (34.3) | 4.5 (−2.0–11.0) | 934 (27.8) | ||
| pT classification | |||||||||
| 1 | 23 (1.3) | 30 (2.6) | < 0.001 | −1.3 (−3.0–0.4) | 10 (1.9) | 6 (3.6) | 0.611 | −1.7 (−6.3–2.9) | 192 (5.7) |
| 2 | 76 (4.2) | 60 (5.1) | −0.9 (−2.5–0.6) | 39 (7.3) | 11 (6.5) | 0.8 (−3.6–5.1) | 360 (10.7) | ||
| 3 | 480 (26.4) | 510 (43.4) | −17.0 (−20.5 to −13.5) | 144 (26.9) | 43 (25.4) | 1.4 (−6.1–9.0) | 990 (29.5) | ||
| 4 | 1242 (68.2) | 576 (49.0) | 19.2 (15.7–22.8) | 343 (64) | 109 (64.5) | −0.5 (−8.8–7.8) | 1818 (54.1) | ||
| pN classification | |||||||||
| 0 | 695 (38.2) | 707 (60.1) | < 0.001 | −22.0 (−25.5 to −18.4) | 45 (8.4) | 28 (16.6) | < 0.001 | −8.2 (−14.2 to −2.1) | 1713 (51.0) |
| 1 | 274 (15.0) | 141 (12.0) | 3.1 (0.6–5.5) | 57 (10.6) | 30 (17.8) | −7.1 (−13.4 to −0.8) | 467 (13.9) | ||
| 2 | 819 (45.0) | 310 (26.4) | 18.6 (15.2–22.0) | 410 (76.5) | 106 (62.7) | 13.8 (5.6–21.9) | 1129 (33.6) | ||
| 3 | 33 (1.8) | 18 (1.5) | 0.3 (−0.6–1.2) | 24 (4.5) | 5 (3.0) | 1.5 (−1.6–4.6) | 51 (1.5) | ||
| pENE | |||||||||
| No | 1267 (69.6) | 966 (82.1) | < 0.001 | −12.6 (−15.6 to −9.5) | 97 (18.1) | 54 (32.0) | < 0.001 | −13.9 (−21.6 to −6.1) | 2596 (77.3) |
| Yes | 554 (30.4) | 210 (17.9) | 12.6 (9.5–15.6) | 439 (81.9) | 115 (68.0) | 13.9 (6.1–21.6) | 764 (22.7) | ||
| LVI | |||||||||
| No | 1092 (60.0) | 838 (71.3) | < 0.001 | −11.3 (−14.7 to −7.9) | 204 (38.1) | 78 (46.2) | 0.061 | −8.1 (−16.7–0.5) | 2293 (68.2) |
| Yes | 729 (40.0) | 338 (28.7) | 11.3 (7.9–14.7) | 332 (61.9) | 91 (53.8) | 8.1 (−0.5–16.7) | 1067 (31.8) | ||
| Laryngectomy | |||||||||
| Subtotal | 154 (8.6) | 125 (10.8) | 0.046 | −2.2 (−4.3–0.0) | 67 (12.7) | 24 (14.5) | 0.550 | −1.7 (−7.7–4.3) | 491 (14.8) |
| Total | 1639 (91.4) | 1033 (89.2) | 2.2 (−0.2–4.5) | 462 (87.3) | 142 (85.5) | 2.2 (−4.1–8.4) | 2816 (85.2) | ||
| Surgical margins | |||||||||
| Negative | 1546 (84.9) | 1054 (89.6) | < 0.001 | −4.7 (−7.1 to −2.3) | 343 (64.0) | 87 (51.5) | 0.004 | 12.5 (4.0–21.1) | 2963 (88.2) |
| Positive | 275 (15.1) | 122 (10.4) | 4.7 (2.3–7.1) | 193 (36.0) | 82 (48.5) | −12.5 (−21.1 to −4.0) | 397 (11.8) | ||
Note: Bolded p–values indicate statistical significance < 0.05.
Abbreviations: aCRT, adjuvant chemoradiotherapy; aRT, adjuvant radiotherapy; CDCS, Charlson–Deyo comorbidity score; IQR, interquartile range; LVI, lymphovascular invasion; pENE, pathologic extranodal extension; pTN, pathologic tumor‐nodal.
3.1. Missed aRT
Out of 3360 patients who met the inclusion criteria, 2997 (89.2%) had one or more indications for receiving adjuvant radiotherapy (aRT)—including pT3‐4 stage, pN2‐3 nodal involvement, lymphovascular invasion (LVI), extranodal extension (pENE), or positive surgical margins (PSM). Among these, 1176 patients (39.2%) did not receive any form of adjuvant therapy and were therefore classified as having missed aRT (Figure 1). Factors associated with increased odds of missing aRT included older age, treatment at an academic/research facility, greater travel distance to the treating facility, and tumors located at other primary sites (p < 0.001). Conversely, patients with pT4 tumors and those with pN1 or pN2 nodal classification had reduced odds of missing aRT (p < 0.001) (Table 2).
TABLE 2.
Univariable and multivariable binary logistic regression models for missed aRT among 3021 patients with consideration(s) for aRT (i.e., pT3‐4, pN2‐3 classification, LVI, pENE, and/or PSM).
| Univariable | p | Multivariable | p | |
|---|---|---|---|---|
| OR (95% CI) | aOR a (95% CI) | |||
| Age at diagnosis (years) | 1.04 (1.03–1.04) | < 0.001 | 1.04 (1.03–1.05) | < 0.001 |
| Sex | ||||
| Male | Ref | |||
| Female | 1.20 (1.00–1.44) | 0.049 | 1.03 (0.82–1.29) | 0.808 |
| Race | ||||
| White | Ref | |||
| Black | 0.83 (0.68–1.01) | 0.067 | ||
| Other | 0.73 (0.45–1.19) | 0.212 | ||
| Primary payer status | ||||
| No insurance | 1.07 (0.78–1.46) | 0.672 | 1.17 (0.81–1.69) | 0.401 |
| Private insurance, managed care | Ref | Ref | ||
| Medicaid | 1.08 (0.87–1.34) | 0.466 | 1.19 (0.93–1.54) | 0.166 |
| Medicare | 1.81 (1.50–2.19) | < 0.001 | 1.23 (0.96–1.58) | 0.102 |
| Reporting facility type | ||||
| Academic/research | 1.55 (1.32–1.81) | < 0.001 | 1.42 (1.18–1.72) | < 0.001 |
| Non‐academic/research | Ref | Ref | ||
| Distance to reporting facility (mi) | 1.00 (1.00–1.01) | < 0.001 | 1.00 (1.00–1.01) | < 0.001 |
| CDCS | ||||
| 0 | Ref | Ref | ||
| 1 | 0.98 (0.81–1.17) | 0.786 | 0.93 (0.75–1.16) | 0.540 |
| 2 | 1.32 (1.04–1.67) | 0.024 | 1.21 (0.92–1.60) | 0.179 |
| Primary site | ||||
| Glottis | Ref | |||
| Supraglottis | 1.05 (0.88–1.26) | 0.584 | 1.08 (0.86–1.37) | 0.501 |
| Subglottis | 0.99 (0.63–1.56) | 0.968 | 1.02 (0.61–1.72) | 0.934 |
| Other | 1.25 (1.02–1.51) | 0.027 | 1.50 (1.18–1.90) | < 0.001 |
| Grade | ||||
| Low | Ref | Ref | ||
| High | 0.82 (0.70–0.97) | 0.020 | 0.86 (0.70–1.05) | 0.136 |
| pT classification | ||||
| 1 | Ref | Ref | ||
| 2 | 0.61 (0.32–1.15) | 0.124 | 0.74 (0.36–1.54) | 0.426 |
| 3 | 0.81 (0.47–1.42) | 0.471 | 0.62 (0.31–1.21) | 0.160 |
| 4 | 0.36 (0.20–0.62) | < 0.001 | 0.24 (0.12–0.48) | < 0.001 |
| pN classification | ||||
| 0 | Ref | Ref | ||
| 1 | 0.51 (0.40–0.64) | < 0.001 | 0.47 (0.35–0.62) | < 0.001 |
| 2 | 0.37 (0.31–0.44) | < 0.001 | 0.38 (0.30–0.50) | < 0.001 |
| 3 | 0.54 (0.30–0.96) | 0.036 | 0.58 (0.27–1.24) | 0.159 |
| pENE | ||||
| No | Ref | Ref | ||
| Yes | 0.50 (0.42–0.59) | < 0.001 | 1.01 (0.78–1.33) | 0.915 |
| LVI | ||||
| No | Ref | Ref | ||
| Yes | 0.60 (0.52–0.71) | < 0.001 | 0.83 (0.68–1.03) | 0.088 |
| Laryngectomy | ||||
| Subtotal | Ref | Ref | ||
| Total | 0.78 (0.61–1.00) | 0.046 | 1.15 (0.82–1.63) | 0.414 |
| Surgical margins | ||||
| Negative | Ref | Ref | ||
| Positive | 0.65 (0.52–0.82) | < 0.001 | 0.85 (0.64–1.12) | 0.236 |
Note: Variables insignificant on univariable regression (p > 0.05) were not included in the multivariable model.
Abbreviations: aCRT, adjuvant chemoradiotherapy; aOR, adjusted odds ratio; aRT, adjuvant radiotherapy; CDCS, Charlson–Deyo comorbidity score; OR, odds ratio; pTN, pathologic tumor‐nodal; Ref, reference.
N = 2453; number of events: 968.
The NCDB encodes reasons why aRT was not administered. Among patients with missed aRT, the most cited reasons were not part of the planned treatment course (N = 792, 67.3%), recommended by physician but refused by patient or family (N = 249, 21.2%), and contraindicated by patient risk factors (N = 47, 4.0%).
3.2. Missed aCRT
Among the 992 patients with consideration(s) for aCRT (i.e., pENE and/or PSM), 169 (17.0%) received adjuvant radiotherapy (aRT) alone and were classified as having missed aCRT (Figure 1). Older age and increased distance to the reporting facility were associated with higher adjusted odds of missed aCRT (p < 0.025) (Table 3).
TABLE 3.
Univariable and multivariable binary logistic regression models for missed aCRT among 1001 patients with consideration(s) for aCRT (i.e., pENE and/or PSM, with or without pT3‐4, pN2‐3 classification, or LVI).
| Univariable | p | Multivariable | p | |
|---|---|---|---|---|
| OR (95% CI) | aOR a (95% CI) | |||
| Age at diagnosis (years) | 1.03 (1.01–1.05) | 0.001 | 1.03 (1.01–1.05) | 0.010 |
| Sex | ||||
| Male | Ref | |||
| Female | 1.47 (0.98–2.20) | 0.059 | ||
| Race | ||||
| White | Ref | |||
| Black | 1.16 (0.74–1.81) | 0.514 | ||
| Other | 0.67 (0.22–2.01) | 0.479 | ||
| Primary payer status | ||||
| No insurance | 1.05 (0.50–2.23) | 0.890 | ||
| Private insurance, managed care | Ref | |||
| Medicaid | 1.16 (0.71–1.90) | 0.550 | ||
| Medicare | 1.54 (0.99–2.41) | 0.057 | ||
| Reporting facility type | ||||
| Academic/research | 0.85 (0.59–1.21) | 0.362 | ||
| Non‐academic/research | Ref | |||
| Distance to reporting facility (mi) | 1.00 (1.00–1.01) | 0.031 | 1.00 (1.00–1.01) | 0.021 |
| CDCS | ||||
| 0 | Ref | |||
| 1 | 1.34 (0.90–1.98) | 0.153 | ||
| 2 | 1.28 (0.73–2.27) | 0.390 | ||
| Primary site | ||||
| Glottis | Ref | |||
| Supraglottis | 0.85 (0.55–1.31) | 0.456 | ||
| Subglottis | 0.67 (0.18–2.50) | 0.552 | ||
| Other | 0.74 (0.45–1.22) | 0.235 | ||
| Grade | ||||
| Low | Ref | |||
| High | 0.82 (0.57–1.18) | 0.294 | ||
| pT classification | ||||
| 1 | Ref | |||
| 2 | 0.47 (0.14–1.58) | 0.223 | ||
| 3 | 0.50 (0.17–1.45) | 0.200 | ||
| 4 | 0.53 (0.19–1.49) | 0.229 | ||
| pN classification | ||||
| 0 | Ref | Ref | ||
| 1 | 0.85 (0.44–1.61) | 0.612 | 0.97 (0.45–2.09) | 0.931 |
| 2 | 0.42 (0.25–0.70) | < 0.001 | 0.55 (0.26–1.14) | 0.105 |
| 3 | 0.33 (0.11–0.98) | 0.046 | 0.59 (0.17–1.99) | 0.395 |
| pENE | ||||
| No | Ref | Ref | ||
| Yes | 0.47 (0.32–0.70) | < 0.001 | 0.70 (0.35–1.39) | 0.303 |
| LVI | ||||
| No | Ref | |||
| Yes | 0.72 (0.51–1.02) | 0.062 | ||
| Laryngectomy | ||||
| Subtotal | Ref | |||
| Total | 0.86 (0.52–1.42) | 0.551 | ||
| Surgical margins | ||||
| Negative | Ref | Ref | ||
| Positive | 1.68 (1.18–2.38) | 0.004 | 1.21 (0.71–2.05) | 0.484 |
Note: Variables insignificant on univariable regression (p > 0.05) were not included in the multivariable model.
Abbreviations: aCRT, adjuvant chemoradiotherapy; aOR, adjusted odds ratio; aRT, adjuvant radiotherapy; CDCS, Charlson–Deyo comorbidity score; LVI, lymphovascular invasion; OR, odds ratio; pENE, pathologic extranodal extension; pTN, pathologic tumor‐nodal; Ref, reference.
N = 614; number of events: 151.
3.3. Reporting Facility Type
Given the unexpected association between academic/research reporting facility and missed aRT, a facility type sub‐analysis was performed (Table S1). Patients treated at academic/research reporting facilities more frequently were of Black race (18.9% vs. 12.5%), insured by Medicaid (26.2% vs. 20.7%), traveled further for treatment (median [IQR] 24 [8–59] vs. 14 [6–33] mi), and had supraglottic tumors (45.4% vs. 40.3%) (p < 0.005). Patients treated at academic/research reporting facilities less often had LVI (30.4% vs. 34.1%) and PSM (10.8% vs. 13.8%) (p < 0.05). pTN classification, pENE, and total laryngectomy utilization did not vary by reporting facility type.
Among patients with consideration(s) for aRT alone, missed aRT remained relatively stable over the study period in both academic/research and non‐academic/research reporting facilities (Figure S1). Among patients with consideration(s) for aCRT, utilization of aCRT increased over the study period in both academic/research and non‐academic/research reporting facilities (Figure S2).
3.4. Adjuvant Therapy by Consideration
Of the 2997 patients with indication(s) for aRT, 1516 (50.6%) only had a stage consideration (i.e., pT3‐4 and/or pN2‐3 classification without LVI, pENE, or PSM), 79 (2.6%) only had a pathologic consideration (i.e., LVI, pENE, and/or PSM without pT3‐4 or pN2‐3 classification), and 1402 (46.8%) had both considerations (Figure 2A). Receipt of aRT was more common among patients with both indications (N = 989, 70.5%) compared to those with stage‐only considerations (N = 810, 53.4%) or pathologic considerations alone (N = 22, 27.8%) (p < 0.001).
FIGURE 2.
(A) Adjuvant radiotherapy utilization by stage consideration only, pathologic consideration only, and both (p < 0.001). (B) Adjuvant chemoradiotherapy utilization among pathologic extranodal extension (pENE) only, positive surgical margins (PSM) only, and both (p < 0.001).
Among 992 patients with consideration(s) for aCRT, 595 (60.0%) had pENE only, 228 (23.0%) had PSM only, and 169 (17.0%) had both (Figure 2B). Patients with pENE only (N = 343, 57.6%) and both considerations (N = 96, 56.8%) underwent aCRT more frequently than those with PSM only (N = 97, 42.5%) (p < 0.001).
3.5. 5‐Year OS
Among 2005 patients with consideration(s) for aRT alone (i.e., pT3‐4, pN2‐3 classification and/or LVI without pENE or PSM), 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 54.2% (N = 889), 61.2% (N = 785), and 61.6% (N = 331), respectively, on Kaplan–Meier analysis (p = 0.002) (Figure 3A). Older age, uninsured, Medicaid, Medicare, CDCS 2, pN1‐3 classification, and missed aRT (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 1.05–1.44) were associated with worse OS on multivariable Cox regression (p < 0.05) (Table 4).
FIGURE 3.
(A) 5‐year overall survival (OS) among 2005 patients with consideration(s) for adjuvant radiotherapy (aRT) alone (p = 0.002). (B) 5‐year OS among 992 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) (p < 0.001).
TABLE 4.
Univariable and multivariable Cox proportional hazard regression models of 5‐year OS among 2020 patients with consideration(s) for aRT alone (i.e., pT3‐4, pN2‐3 classification, and/or LVI without pENE or PSM).
| Univariable | p | Multivariable | p | |
|---|---|---|---|---|
| HR (95% CI) | aHR a (95% CI) | |||
| Age at diagnosis (years) | 1.04 (1.03–1.04) | < 0.001 | 1.04 (1.03–1.04) | < 0.001 |
| Sex | ||||
| Male | Ref | |||
| Female | 1.10 (0.92–1.31) | 0.290 | ||
| Race | ||||
| White | Ref | |||
| Black | 0.87 (0.72–1.05) | 0.139 | ||
| Other | 0.81 (0.50–1.32) | 0.403 | ||
| Primary payer status | ||||
| No insurance | 1.44 (1.08–1.93) | 0.014 | 1.68 (1.25–2.26) | < 0.001 |
| Private insurance, managed care | Ref | Ref | ||
| Medicaid | 1.36 (1.10–1.69) | 0.005 | 1.51 (1.22–1.88) | < 0.001 |
| Medicare | 2.03 (1.68–2.45) | < 0.001 | 1.34 (1.08–1.66) | 0.007 |
| Reporting facility type | ||||
| Academic/research | 1.03 (0.89–1.20) | 0.660 | ||
| Non‐academic/research | Ref | |||
| Distance to reporting facility (mi) | 1.00 (1.00–1.00) | 0.067 | ||
| CDCS | ||||
| 0 | Ref | Ref | ||
| 1 | 1.21 (1.03–1.43) | 0.021 | 1.18 (0.99–1.39) | 0.058 |
| 2 | 1.39 (1.13–1.71) | 0.002 | 1.41 (1.14–1.75) | 0.002 |
| Primary site | ||||
| Glottis | Ref | Ref | ||
| Supraglottis | 1.15 (0.97–1.36) | 0.105 | 1.03 (0.86–1.24) | 0.761 |
| Subglottis | 1.04 (0.69–1.57) | 0.850 | 1.05 (0.70–1.60) | 0.806 |
| Other | 1.20 (1.01–1.44) | 0.043 | 1.17 (0.97–1.41) | 0.101 |
| Grade | ||||
| Low | Ref | |||
| High | 1.12 (0.96–1.31) | 0.150 | ||
| pT classification | ||||
| 1 | Ref | |||
| 2 | 1.39 (0.65–2.98) | 0.396 | ||
| 3 | 1.21 (0.62–2.35) | 0.575 | ||
| 4 | 1.35 (0.70–2.62) | 0.368 | ||
| pN classification | ||||
| 0 | Ref | Ref | ||
| 1 | 1.49 (1.23–1.82) | < 0.001 | 1.53 (1.25–1.89) | < 0.001 |
| 2 | 1.86 (1.59–2.18) | < 0.001 | 2.13 (1.78–2.56) | < 0.001 |
| 3 | 2.06 (0.66–6.42) | 0.211 | 3.38 (1.07–10.66) | 0.037 |
| LVI | ||||
| No | Ref | Ref | ||
| Yes | 1.22 (1.05–1.42) | 0.011 | 0.94 (0.80–1.11) | 0.487 |
| Laryngectomy | ||||
| Subtotal | Ref | |||
| Total | 1.30 (0.98–1.73) | 0.069 | ||
| Adjuvant therapy | ||||
| None | 1.27 (1.09–1.48) | 0.002 | 1.23 (1.05–1.44) | 0.011 |
| aRT alone | Ref | Ref | ||
| aCRT | 0.99 (0.81–1.22) | 0.932 | 0.80 (0.65–1.00) | 0.051 |
Note: Variables insignificant on univariable regression (p > 0.05) were not included in the multivariable model.
Abbreviations: aCRT, adjuvant chemoradiotherapy; aHR, adjusted hazard ratio; aRT, adjuvant radiotherapy; CDCS, Charlson–Deyo comorbidity score; HR, hazard ratio; LVI, lymphovascular invasion; OS, overall survival; pENE, pathologic extranodal extension; PSM, positive surgical margins; pTN, pathologic tumor‐nodal; Ref, reference.
N = 1938; number of uncensored deaths: 780.
Among 992 patients with consideration(s) for aCRT, 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 33.3% (N = 287), 36.7% (N = 169), and 38.8% (N = 536), respectively, on Kaplan–Meier analysis (p < 0.001) (Figure 3B). On multivariable Cox regression, older age, Medicaid, pN2‐3 classification, pENE, LVI, PSM, and missed aRT (aHR 1.85, 95% CI 1.52–2.24) were associated with worse OS (p < 0.05) (Table 5). Missed aCRT (aHR 1.24, 95% CI 0.98–1.56, p = 0.072) was not associated with worse OS.
TABLE 5.
Univariable and multivariable Cox proportional hazard regression models of 5‐year OS among 1001 patients with consideration(s) for aCRT (i.e., pENE and/or PSM, with or without pT3‐4, pN2‐3 classification, or LVI).
| Univariable | p | Multivariable | p | |
|---|---|---|---|---|
| HR (95% CI) | aHR a (95% CI) | |||
| Age at diagnosis (years) | 1.02 (1.01–1.03) | < 0.001 | 1.02 (1.01–1.03) | < 0.001 |
| Sex | ||||
| Male | Ref | Ref | ||
| Female | 0.81 (0.66–0.99) | 0.036 | 0.87 (0.71–1.07) | 0.183 |
| Race | ||||
| White | Ref | |||
| Black | 1.15 (0.93–1.43) | 0.203 | ||
| Other | 0.96 (0.56–1.63) | 0.868 | ||
| Primary payer status | ||||
| No insurance | 1.24 (0.86–1.78) | 0.241 | 1.17 (0.81–1.69) | 0.414 |
| Private insurance, managed care | Ref | Ref | ||
| Medicaid | 1.31 (1.04–1.65) | 0.023 | 1.32 (1.04–1.67) | 0.025 |
| Medicare | 1.44 (1.17–1.78) | < 0.001 | 1.12 (0.89–1.42) | 0.326 |
| Reporting facility type | ||||
| Academic/research | 1.08 (0.91–1.28) | 0.395 | ||
| Non‐academic/research | Ref | |||
| Distance to reporting facility (mi) | 1.00 (1.00–1.00) | 0.464 | ||
| CDCS | ||||
| 0 | Ref | |||
| 1 | 1.03 (0.85–1.24) | 0.783 | ||
| 2 | 1.00 (0.77–1.31) | 0.977 | ||
| Primary site | ||||
| Glottis | Ref | Ref | ||
| Supraglottis | 0.77 (0.62–0.94) | 0.013 | 0.94 (0.75–1.17) | 0.560 |
| Subglottis | 0.85 (0.50–1.46) | 0.563 | 0.80 (0.46–1.40) | 0.432 |
| Other | 0.94 (0.75–1.19) | 0.619 | 0.99 (0.78–1.26) | 0.920 |
| Grade | ||||
| Low | Ref | |||
| High | 1.15 (0.98–1.36) | 0.091 | ||
| pT classification | ||||
| 1 | Ref | Ref | ||
| 2 | 1.39 (0.95–2.02) | 0.092 | 0.73 (0.36–1.49) | 0.384 |
| 3 | 2.01 (1.43–2.81) | < 0.001 | 1.19 (0.61–2.31) | 0.613 |
| 4 | 2.25 (1.62–3.11) | < 0.001 | 1.66 (0.85–3.24) | 0.136 |
| pN classification | ||||
| 0 | Ref | Ref | ||
| 1 | 1.93 (1.33–2.81) | 0.001 | 1.52 (0.99–2.35) | 0.057 |
| 2 | 2.67 (1.96–3.64) | < 0.001 | 2.13 (1.41–3.22) | < 0.001 |
| 3 | 3.47 (2.19–5.50) | < 0.001 | 2.72 (1.58–4.68) | < 0.001 |
| pENE | ||||
| No | Ref | Ref | ||
| Yes | 1.88 (1.52–2.33) | < 0.001 | 1.45 (1.04–2.02) | 0.030 |
| LVI | ||||
| No | Ref | Ref | ||
| Yes | 1.47 (1.24–1.73) | < 0.001 | 1.22 (1.02–1.47) | 0.027 |
| Laryngectomy | ||||
| Subtotal | Ref | Ref | ||
| Total | 2.07 (1.56–2.73) | < 0.001 | 1.23 (0.89–1.71) | 0.212 |
| Surgical margins | ||||
| Negative | Ref | Ref | ||
| Positive | 0.80 (0.68–0.95) | 0.010 | 1.26 (1.01–1.55) | 0.036 |
| Adjuvant therapy | ||||
| None | 1.47 (1.23–1.77) | < 0.001 | 1.85 (1.52–2.24) | < 0.001 |
| aRT alone | 1.13 (0.91–1.41) | 0.272 | 1.24 (0.98–1.56) | 0.072 |
| aCRT | Ref | Ref | ||
Note: Variables insignificant on univariable regression (p > 0.05) were not included in the multivariable model.
Abbreviations: aCRT, adjuvant chemoradiotherapy; aHR, adjusted hazard ratio; aRT, adjuvant radiotherapy; CDCS, Charlson–Deyo comorbidity score; HR, hazard ratio; LVI, lymphovascular invasion; OS, overall survival; pENE, pathologic extranodal extension; PSM, positive surgical margins; pTN, pathologic tumor‐nodal.
N = 947; number of uncensored deaths: 574.
3.6. Total Laryngectomy Sub‐Analysis
2816 (85.2%) patients underwent total laryngectomy. Among 2672 (94.9%) patients with consideration(s) for aRT, 1033 (36.7%) missed aRT. Among 850 patients with consideration(s) for aCRT, 142 (16.7%) missed aCRT. Total laryngectomy was not associated with missed aRT or missed aCRT (Tables 2 and 3).
Among 1822 patients with consideration(s) for aRT alone, 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 53.2% (N = 787), 60.7% (N = 730), and 60.5% (N = 305), respectively, on Kaplan–Meier analysis (p = 0.002). Among 850 patients with consideration(s) for aCRT, 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 26.7% (N = 246), 33.9% (N = 142), and 37.1% (N = 462), respectively, on Kaplan–Meier analysis (p < 0.001). Total laryngectomy was not associated with OS on multivariable Cox regression for either consideration group (Tables 4 and 5).
3.7. Landmark Survival Analysis
202 (6.0%) patients had survival time < 6 months. After censoring survival time < 6 months, among patients with consideration(s) for aRT alone, 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 59.3%, 61.7%, and 62.5%, respectively, on Kaplan–Meier analysis (p = 0.579); on multivariable Cox regression, missed aCRT (aHR 0.78, 95% CI 0.63–0.98, p = 0.031) was associated with worse OS. Missed aRT (aHR 1.05, 95% CI 0.89–1.24, p = 0.595) was not associated with OS.
Among patients with consideration(s) for aCRT, 5‐year OS for patients undergoing no adjuvant therapy, aRT alone, and aCRT was 43.1%, 38.7%, and 39.8%, respectively, on Kaplan–Meier analysis (p = 0.706); missed aRT (aHR 1.33, 95% CI 1.07–1.66, p = 0.012) was associated with worse OS on multivariable Cox regression. Missed aCRT (aHR 1.21, 95% CI 0.95–1.54, p = 0.123) was not associated with OS.
4. Discussion
Upfront laryngectomy remains a treatment option for advanced LSCC, and several clinical trials demonstrate the survival benefit of timely adjuvant therapy delivered in the presence of high‐risk pathologic features [26, 27, 28, 29, 30]. Adherence to evidence‐based recommendations, although challenging, reflects the quality of care that a treatment facility can provide [48, 49, 50]. Our study investigating adjuvant therapy following upfront laryngectomy for LSCC suggests that deviations from evidence‐based recommendations occur frequently and portend worse OS.
Patients at risk of missed aRT were older, treated at academic/research facilities, and traveled further for treatment. Older age and distance to the reporting facility were also associated with missed aCRT, likely related to age‐related desire to balance quality of life and disease prognosis with treatment‐induced toxicities [51, 52, 53, 54, 55]. In addition, adjuvant therapy requiring frequent visits to the treatment facility may disadvantage patients facing longer commutes and influence treatment decisions [56, 57, 58]. Non‐academic/research facilities had decreased adjusted odds of missed aRT, possibly related to patients treated at academic/research facilities traveling further for treatment, or academic/research facilities providing care to underserved patient populations with limited income and reliance on public transportation. Across both facility types, treatment adherence typically improved over the study period. Interestingly, studies of oral cavity squamous cell carcinoma (SCC), human papillomavirus‐positive (HPV) oropharyngeal SCC, and major salivary gland cancer (MSGC) utilizing the NCDB have also associated academic/research facilities with missed adjuvant therapy [26, 33, 35]. Although a minority of patients in our cohort underwent upfront laryngectomy and aRT at different facilities (543 out of 1853 patients [29.3%]), studies of HNC have associated fragmented care with delayed or entirely missed aRT [59, 60]. Unsurprisingly, high pTN classification was associated with delivery of aRT, aligning with NCCN guidelines.
Most patients missed aRT because it was not part of the planned treatment course. Although the collection and reliability of this variable in the NCDB must be critically questioned, national practice patterns following upfront laryngectomy for LSCC may deviate from NCCN guidelines, possibly related to various patient factors (i.e., feeding tube dependence, tracheostomy, and postoperative rehabilitation) that impact coordination of care and feasibility of undergoing aRT [26, 33]. Deviations, except in the circumstances of clinical trials, should be rare, but may occur more frequently than previously assumed. In a retrospective review of 150 patients with HNC, approximately 40% of patients underwent adjuvant therapy deviating from NCCN guidelines [34]. Studies of oral cavity SCC, HPV‐positive oropharyngeal SCC, and MSGC utilizing the NCDB document 28%, 29%, and 18% of patients, respectively, missing aRT and having worse OS [26, 33, 35]. The considerably higher rate of missed aRT in our study (39%) suggests that patients undergoing upfront laryngectomy for LSCC may benefit from targeted initiatives promoting guideline‐directed management.
Patients with high pTN classification as the only consideration for aRT underwent aRT more frequently than those with pathologic markers (i.e., pENE, LVI, and/or PSM) as the only consideration, suggesting that one consideration does not drive treatment decisions more strongly than the other. Patients with pENE as the only consideration for aCRT underwent aCRT more frequently than those with PSM as the only consideration, suggesting that pENE drives adjuvant chemotherapy utilization more strongly than PSM; similar findings have been noted in NCDB analyses of oral cavity SCC, HPV‐positive oropharyngeal SCC, and MSGC [26, 33, 35].
Among patients with consideration(s) for aRT alone and those with consideration(s) for aCRT, missed adjuvant therapy was associated with worse OS, even after censoring survival time < 6 months, consistent with the findings of landmark HNC clinical trials [26, 27, 28, 29, 30, 46, 47]. These findings emphasize the importance of delivering adjuvant therapy in accordance with evidence‐based recommendations.
This retrospective analysis of NCDB data is subject to certain limitations, including the potential for inaccuracies in histologic classification and inconsistencies in coding practices across reporting institutions. The NCDB collects data from a predetermined group of CoC‐accredited facilities; patients lacking access to CoC‐accredited facilities or preferring to undergo treatment at another facility introduce geographic selection bias. The NCDB does not report specific comorbidities, tobacco and alcohol use, medications, social determinants of health, history of neck irradiation, PNI, imaging, multidisciplinary tumor board recommendations, performance status, quality of life, goals of care, re‐resection for PSM, treatment toxicity, completion, interruptions, failures, disease progression, locoregional recurrence, and disease‐free survival, limiting our analysis to OS. Although primary chemoradiotherapy is the preferred initial treatment of most LSCC, the NCDB does not accurately differentiate primary and adjuvant radiotherapy doses, limiting our analysis to upfront laryngectomy. Missed adjuvant therapy is highly multifactorial and related to physician‐patient miscommunication, inadequate social support, and delayed or incomplete therapy, but variables necessary in making these inferences are also not reported in the NCDB. Recommendations proposed by the NCCN and other advisory committees are often updated frequently; as recommendations change, the number of patients recommended for and then undergoing adjuvant therapy also changes, complicating longitudinal retrospective analysis.
5. Conclusion
Approximately 40% of patients undergoing upfront laryngectomy for LSCC missed aRT. Patients at risk of missing aRT were older, treated at academic/research facilities, and traveled further for treatment. Approximately 17% of patients missed aCRT; patients at risk of missing aCRT were older and traveled further for treatment. Compared with other pathologic considerations (i.e., LVI and PSM), high pTN classification and pENE appear to be the primary drivers of adjuvant therapy utilization. Missed aRT was associated with worse OS. Continued monitoring of national practice patterns may identify risk factors for off‐guideline management and create opportunities for quality improvement in the multidisciplinary care of patients undergoing upfront laryngectomy for LSCC.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: (A) Adjuvant therapy among 1309 patients with consideration(s) for adjuvant radiotherapy (aRT) alone who received treatment at an academic/research facility by year of diagnosis. (B) Adjuvant therapy among 669 patients with consideration(s) for adjuvant radiotherapy (aRT) alone who received treatment at a non‐academic/research facility by year of diagnosis.
Figure S2: (A) Adjuvant therapy among 648 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) who received treatment at an academic/research facility by age at diagnosis. (B) Adjuvant therapy among 331 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) who received treatment at a non‐academic/research facility by age at diagnosis.
Table S1: Patient demographics, clinicopathologic features, and adjuvant therapy by facility type, n (%).
Patel A. M., Haleem A., Kaki P. C., Bahethi R., Baredes S., and Park R. C. W., “Missed Adjuvant Therapy Following Upfront Laryngectomy for Laryngeal Squamous Cell Carcinoma,” Laryngoscope Investigative Otolaryngology 10, no. 5 (2025): e70276, 10.1002/lio2.70276.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: (A) Adjuvant therapy among 1309 patients with consideration(s) for adjuvant radiotherapy (aRT) alone who received treatment at an academic/research facility by year of diagnosis. (B) Adjuvant therapy among 669 patients with consideration(s) for adjuvant radiotherapy (aRT) alone who received treatment at a non‐academic/research facility by year of diagnosis.
Figure S2: (A) Adjuvant therapy among 648 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) who received treatment at an academic/research facility by age at diagnosis. (B) Adjuvant therapy among 331 patients with consideration(s) for adjuvant chemoradiotherapy (aCRT) who received treatment at a non‐academic/research facility by age at diagnosis.
Table S1: Patient demographics, clinicopathologic features, and adjuvant therapy by facility type, n (%).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.