Delays Starting Postoperative Radiotherapy Among Head and Neck Cancer Patients: A Systematic Review and Meta-Analysis

Abstract

Objective:

Initiating postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery is the first and only Commission on Cancer (CoC) approved quality metric for head and neck squamous cell carcinoma (HNSCC). No study has systematically reviewed nor synthesized the literature to establish national benchmarks for delays in starting PORT.

Data sources:

Following PRISMA guidelines, we performed a systematic review of PubMed, Scopus, and CINAHL.

Review Methods:

Studies that described time-to-PORT or PORT delays in patients with HNSCC treated in the US after 2003 were included. Meta-analysis of proportions and continuous measures was performed on non-overlapping datasets to examine the pooled frequency of PORT delays and time-to-PORT.

Results:

36 studies were included in the systematic review and 14 in the meta-analysis. Most studies utilized single-institution (n=17; 47.2%) or cancer registry (n=16; 44.4%) data. Twenty-five studies (69.4%) defined PORT delay as >6 weeks after surgery (the definition utilized by the CoC and NCCN Guidelines), whereas 4 (11.1%) defined PORT delay as a time interval other than >6 weeks, and 7 (19.4%) characterized time-to-PORT without defining delay. Meta-analysis revealed that 48.6% (95% CI, 41.4% to 55.9%) of patients started PORT >6 weeks after surgery. Median and mean time-to-PORT was 45.8 days (95% CI, 42.4 to 51.4 days) and 47.4 days (95% CI, 43.4 to 51.4 days) respectively.

Conclusion:

Delays in initiating guideline-adherent PORT occur in approximately half of patients with HNSCC. These meta-analytic data can be used to set national benchmarks and assess progress in reducing delays.

Introduction

In November 2021, the American College of Surgeons/Commission on Cancer (CoC) established initiation of postoperative radiotherapy (PORT) within 6 weeks (42 days) of surgery for head and neck squamous cell carcinoma (HNSCC) as its first and only quality metric for this disease.¹ The CoC formulates standards to ensure the delivery of quality, comprehensive cancer care with an aim to improve survival and quality of life for patients with cancer. This CoC quality metric, which coincides with the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines,² was chosen because of (1) the association between starting PORT within 6 weeks of surgery and improved locoregional control and survival for patients with HNSCC;^3–15 (2) disproportionate burden of delays in starting PORT on medically vulnerable populations and subsequent disparities in quality and outcomes; and (3) documented gaps in quality of care/performance of this potential metric. Furthermore, timely initiation of PORT involves coordinating care amongst many specialties and has the potential to enhance collaborative and integrated multi-disciplinary care.^{1,4–7,16–21}

Although timely PORT initiation has been associated with improved HNSCC outcomes and survival, treatment delays in HNSCC are common.^{7–10,12,13,16,17,22–24} Accurate estimation of the frequency of PORT delay is important to provide benchmarks for assessing progress regarding the CoC quality metric. However, the landscape of data in currently published studies describing PORT delay frequency and/or variability in PORT delays across diverse care delivery settings (e.g., clinical trials, academic centers, community hospitals, VA medical centers) has not been systematically characterized. Therefore, we conducted this systematic review and meta-analysis to describe the frequency of PORT delay nationally and assess variability across care delivery settings.

Methods

Information Source and Search Strategy

This review was registered with the Prospective Register of Systematic Reviews (PROSPERO CRD42022378519). The information is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.²⁵ To identify studies for inclusion in this review, a research informationist (E.A.B.) with expertise in conducting systematic reviews developed detailed search strategies in the following three databases: PubMed (U.S. National Library of Medicine, National Institutes of Health), CINAHL Complete (EBSCOhost), and Scopus (Elsevier) (Appendix A). The search strategies used a combination of subject headings (e.g., MeSH in PubMed) and keywords for the concepts of post-operative radiation therapy, head and neck cancer, and delays. The PubMed search strategy was modified for the other two databases, maintaining similar keywords, and replacing MeSH terms with appropriate subject headings, when available. The databases were searched from inception through December 2, 2022 with an English language filter. Search strategies were peer reviewed by a second librarian using a modified PRESS peer review form.

Study Selection for Inclusion in Systematic Review

Articles were analyzed using the review management software Covidence (Veritas Health Innovation Ltd, Melbourne, Australia). The eligibility criteria for inclusion in the review are outlined in Table 1. Because the CoC and NCCN guidelines only apply to the US, and other countries have various care delivery models, studies that treated patients outside of the US were excluded. Studies with patients treated before 2004 were also excluded to align with the era of adjuvant chemoradiotherapy^26,27 and modern radiotherapy techniques.^28,29 Following the initial search, abstracts were reviewed by two authors (K.A.D. and E.M.G.). For the abstracts that were not excluded, full-text articles were independently assessed for eligibility by the same two reviewers. Conflicts were resolved with discussion and consensus. Two authors (K.A.D. and E.M.G.) also reviewed the reference lists of the included publications to detect additional potentially eligible articles.

Table 1.

Study Eligibility Criteria for Inclusion into the Systematic Review

Study Inclusion Criteria	Study Exclusion Criteria
(1) Original peer-reviewed publications (2) Included patients with SCC of the oral cavity, oropharynx, hypopharynx, or larynx who underwent surgery and PORT (3) Reported either a frequency of PORT delay (with a definition of how delay was defined) or time-to-PORT	(1) Patients treated outside of the US (2) Patients treated before 2004 (3) >10% of patients with surgery and PORT had non-HNSCC histology or non-mucosal HNSCC (4) No full text available for review (5) Non-English language (6) Review articles (7) Duplication of studies or secondary analysis of the same group of patients

Quality Assessment

The Oxford Centre for Evidence-Based Medicine (OCEBM) criteria were utilized to assess the evidence level of included articles.³⁰ Following the Cochrane Handbook for Systematic Reviews of Interventions Version 6.3,³¹ the Risk of Bias in Non-Randomized Studies of-Exposure (ROBINS-E) tool was utilized to assess the risk of bias.³² Each study was graded as either “low”, “moderate”, or “serious” risk of bias according to standard categories. Two authors (K.A.D. and M.F.K.) individually evaluated each study and compared results, with all disagreements being resolved by a third author (E.M.G.).

Data Items and Data Collection Process

Variables to be extracted and definitions for categorization were defined a priori. Two authors (K.A.D. and M.F.K.) independently extracted data from each publication then compared results to optimize accuracy. Discrepancies were addressed by discussion and consensus. The primary outcomes of interest were (1) frequency of PORT delay and (2) time-to-PORT initiation. For studies that reported a frequency of PORT delay, we utilized the definition of PORT delay selected by the author, recorded the rationale/derivation of that definition of delay, and reported results as a percentage. The derivation of the definition of PORT delay was classified as prespecified (e.g., adherent to NCCN Guidelines), empirical (e.g., based on the median or quartiles of the study sample), or derived (e.g., from recursive partition analysis showing a difference in outcomes). Time-to-PORT (in days) was reported as mean and standard deviation (SD), median and interquartile range (IQR), and/or minimum and maximum range. Author, publication year, study design and OCEBM evidence level, data source, characteristics of study population, number of patients who underwent surgery and PORT, number of patients with PORT delay, and year(s) of diagnosis and/or treatment were extracted. Data source was categorized as single- or multi-institutional analysis, cancer registry, or database. For single- and multi-institutional studies, the facility type (e.g., academic center, VA Medical Center, county hospital) was also collected. Data collection and analysis occurred from December 1, 2022 until April 11, 2023. For publications that met inclusion criteria but had incomplete or unclear data, we contacted corresponding authors via e-mail to request the necessary data. All queries were answered, and no studies were excluded due to incomplete or missing data.

Study Selection for Meta-Analysis

To minimize duplication of studies analyzing the same patients, only one National Cancer Database (NCDB) study was included in the meta-analysis. To be aligned with the CoC metric (which applies to mucosal HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx), we considered only the NCDB studies that included patients evaluating all HNSCC subsites. Of those, we then selected the study that was the most inclusive regarding years that the included patients underwent surgery and PORT. To ensure that meta-analytic findings were not driven by the disproportionately large sample size of the included NCDB study, we also performed a sensitivity meta-analysis of proportions and mean time-to-PORT excluding the NCDB study. For the studies that described an intervention to reduce PORT delay, only data from the pre-intervention cohort were included in the meta-analysis. Of the 25 studies that reported frequency of PORT delay defined at > 6 weeks, the following were excluded from meta-analysis: 10 were excluded to minimize duplication of patients included in the NCDB,^{6,7,17,33–39} and 1 was excluded for including a heterogeneous patient population and providing insufficient details about PORT.⁴⁰

Data Analysis and Synthesis of Results (Statistical Analysis)

Categorical variables were summarized by frequency and percentage, and continuous variables were summarized by mean ± standard deviation (SD) or median and 25^th – 75^th interquartile range (25-75 IQR). Meta-analysis of continuous measures (age, mean and median time-to-PORT) were performed by Comprehensive Meta-Analysis version 3 (Biostat Inc, Englewood, NJ, USA). Meta-analysis of proportions (frequency of PORT delay and patient characteristics) were performed using MedCalc 20.218 (MedCalc Software, Ostend, Belgium). Each measure (mean/proportion and 95% confidence interval (CI) was weighted according to the number of patients affected. Heterogeneity among studies was assessed using χ2 and I² statistics with fixed effects (I² < 50%) and random effects (I² > 50%).^41,42 Potential publication bias was evaluated by visual inspection of the funnel plot and Egger’s regression test, which statistically examines the asymmetry of the funnel plot.^43,44 A p-value of <0.05 was considered statistically significant.

Results

Study Characteristics

The literature search returned 670 unique articles. During title and abstract screening, 593 articles were excluded, leaving 77 studies assessed in full text. Two additional articles were identified by hand searching reference lists. A total of 36 articles were included in the systematic review. The PRISMA diagram, which outlines the search and screening process, is displayed in Figure 1. Articles selected for inclusion were level 2 and level 4 studies based on the Oxford Level of Evidence and were published between 2011 and 2022. Descriptive features of the included studies are summarized in Tables 2–4.

Figure 1.

PRISMA Flow Diagram of Study Selection

HNSCC= Head and neck squamous cell carcinoma; PORT= Postoperative Radiotherapy

Table 2.

Characteristics of Included Studies with PORT Delay Defined as >6 weeks.

Author, Year	Study Design, OLE	Data Source/Facility Type	Patient Population	Years of Diagnosis or Treatment	Sample Size, No.a	PORT Delay Definition and Derivation	Freq of PORT Delay, %	Time to PORT, days
HNSCC
Cramer et al,7 2017	RCo, 2b	NCDB	HNSCC (excluding HPV+ OPSCC)	2004-2014	40,293	>6wk, NCCN guidelines	55.5	N/A
Graboyes et al,17 2017a	RCo, 2b	NCDB	HNSCC	2006-2014	41,291	>6wk, NCCN guidelines	55.3	N/A
Graboyes et al,6 2017b	RCo, 2b	NCDB	HNSCC	2006-2014	47,273	>6wk, NCCN guidelines	55.7	N/A
Harris et al,34 2018	RCo, 2b	NCDB	HNSCC, AJCC 7th edition stage III-IV	2004-2013	25,216	>6wk, NCCN guidelines	61.3	N/A
Janz et al,16 2018	RCo, 2b	Single Institution, academic	HNSCC	2014-2016	197	>6wk, NCCN guidelines	45.2	Median 42 (R 13 to 123)
Levy et al,22 2020	RCo, 2b	NCDB	HNSCC	2004-2015	60,776	>6wk, NCCN guidelines	56.0	Median 46 (IQR 35 to 61)b
Mazul et al,36 2020	RCo, 2b	NCDB	HNSCC	2010-2015	38,520	>6wk, NCCN guidelines	59.4	N/A
Sykes et al,23 2020	RCo, 2b	Single Institution, academic	HNSCC	2015-2016	26	>6wk, NCCN guidelines	57.7	Median 45 (IQR 39 to 55)b
Subsite-specific
Amini et al,33 2019	RCo, 2b	NCDB	OCSCC	2004-2013	10,212	>6wk, NCCN guidelines	69.2	N/A
Divi et al,55 2018	Cohort trial, 2b	Single Institution, academic	OCSCC with surgery and PORT at same facility	2014-2016	34	>6wk, NCCN guidelines	38.2	Median 41 (IQR 35 to 48)
Fullmer et al,58 2020	RCo, 2b	Single Institution, county hospital	Laryngeal SCC	2005-2015	58	>6wk, NCCN guidelines	75.9	Mean 67.8 ± 36.6b
Hernandez et al, 202157	RCo, 2b	Single institution, VAMC	OCSCC or high-risk OPSCC	2017-2021	32	>6wk, NCCN guidelines	28.1	Mean 41 ± 9.7b
Morse et al,37 2018a	RCo, 2b	NCDB	Laryngeal SCC	2004-2013	5,154	>6wk, NCCN guidelines	48.0	Median 42
Morse et al,38 2018b	RCo, 2b	NCDB	OPSCC	2010-2013	2,920	>6wk, NCCN guidelines	48.0	Median 42
Treatment-specific
Boukovalas et al,40 2020	RCo, 2b	Single Institution, academic	Laryngeal SCC treated with TL	2008-2013	201	>6wk, NCCN guidelines	55.7c	N/A
Carpenter et al,52 2014	RCS, 4	Single Institution, academic	HNSCC treated with TORS	2007-2012	33	>6wk, NCCN guidelines	36.4	Median 41 (R 24 to 60)
Ghanem et al,60 2019	RCo, 2b	Single Institution, academic	HNSCC treated with adjuvant CRT	2010-2015	103	>6wk, NCCN guidelines	33.0	N/A
Jin et al,35 2020	RCo, 2b	NCDB	HNSCC treated with adjuvant proton or photon RT	2004-2015	42,890	>6wk, NCCN guidelines	63.2	Proton RT Median 62, Photon RT Median 48
Mascarella et al,61 2022	PCo, 2b	Single Institution, academic	HNSCC undergoing microvascular reconstruction	2018-2020	97	>6wk, NCCN guidelines	33.0	N/A
Pang et al,54 2019	RCS, 4	Multi-institutional, 3 academic centers	HNSCC undergoing submandibular gland transfer	2004-2017	19	>6wk, NCCN guidelines	31.6	Median 33 (IQR 28 to 47)
Strohl et al,19 2019	RCo, 2b	Single Institution, academic	OCSCC undergoing free flap & dental extraction	2007-2017	34	>6wk, NCCN guidelines	55.9	Range 27 to 168
Voora et al,3 2021	Cohort trial, 2b	Single Institution, academic	HNSCC undergoing free flap reconstruction w/o major complication	2017-2019	19	>6wk, NCCN guidelines	89.5	N/A
Other Patient Population
Itamura et al,59 2020	RCo, 2b	Single Institution, academic	HNSCC with HMO, PPO, or Medicare insurance	2014-2017	104	>6wk, NCCN guidelines	54.8	Mean 47.4 ± 15.7
Lau et al,53 2011	RCS, 4	Single Institution, academic	HNSCC with orocutaneous or pharyngocutaneous fistula at PORT start	2004-2008	17	>6wk, NCCN guidelines	47.1	Median 39 (IQR 33 to 52.5)
Pang et al,39 2021	RCo, 2b	NCDB	HNSCC, ≥40yo, excluding patients in 6 late Medicaid expansion states	2004-2015	11,717	>6wk, NCCN guidelines	66.5	N/A

AJCC= American Joint Committee on Cancer; CRT= chemoradiotherapy; Freq= Frequency; HNSCC= Head and Neck Squamous Cell Carcinoma; HMO=Health Maintenance Organization; HPV= Human papillomavirus; IQR= Interquartile range; N/A= Not applicable; NCCN= National Comprehensive Cancer Network; NCDB=National Cancer Database; OLE= Oxford Level of Evidence; OCSCC=Oral Cavity Squamous Cell Carcinoma; OPSCC=Oropharyngeal Squamous Cell Carcinoma; PCo= Prospective cohort; PPO=Preferred Provider Organization; PORT= Postoperative radiotherapy; R=Range; RCS=Retrospective case series; RCo= Retrospective cohort; RT= Radiation Therapy; SCC= Squamous Cell Carcinoma; TL=Total laryngectomy; TORS=TransOral Robotic Surgery; VAMC=Veteran’s Administration Medical Center;

^a=Sample size=number of patients in the study with surgery and PORT for the treatment of HNSCC. This n may not be same # as overall n included in the study;

^bData clarification provided by authors;

^c=includes adjuvant RT and/or chemotherapy

Table 4.

Characteristics of Included Studies that Reported Time-to-PORT without Defining Delay.

Author, Year	Study Design, OLE	Data Source/Facility Type	Patient Population	Years of Diagnosis or Treatment	Sample Size, No.a	PORT Delay Definition, days	Derivation of Delay Definition	Freq of Delay, %	Time to PORT, days
HNSCC
Goel et al,46 2019a	RCo, 2b	NCDB	HNSCC	2004-2014	35,167	N/A	N/A	N/A	Median 48 (IQR 38 to 62)
Guttmann et al,47 2018	RCo, 2b	NCDB	HNSCC, AJCC 7th edition stage III-IV	2004-2012	15,234	N/A	N/A	N/A	Mean 47 ± 21
Subsite-specific
Chen et al,8 2018	RCo, 2b	Single Institution, academic	OCSCC	2008-2016	132	N/A	N/A	N/A	Mean 45.2 ± 14.6
Factor et al,45 2020	RCS, 4	Single Institution, academic	Buccal or RMT SCC	2008-2018	27	N/A	N/A	N/A	Median 50 (R 32 to 133)
Ghanem et al,56 2022	RCo, 2b	Multi-institutional, 6 academic centers	OCSCC treated with adjuvant CRT	2005-2015	187	N/A	N/A	N/A	Median 51 (R 29 to 109)
Treatment-specific
Chao et al,9 2019	RCo, 2b	Single Institution, academic	HPV+ OPSCC treated with TORS	2010-2015	267	N/A	N/A	N/A	Median 59 (IQR 48 to 69)
Tam et al,10 2018	RCo, 2b	NCDB	HNSCC treated with adjuvant CRT	2005-2012	16,733	N/A	N/A	N/A	Median 45 (IQR 34 to 61)

AJCC= American Joint Committee on Cancer; CRT= chemoradiotherapy; Freq= Frequency; HNSCC= head and neck squamous cell carcinoma; N/A= not applicable; NCDB=National Cancer Database; HPV= Human papillomavirus; IQR= Interquartile range; OCSCC=Oral Cavity Squamous Cell Carcinoma; OLE= Oxford Level of Evidence; OPSCC= Oropharyngeal Squamous Cell Carcinoma; PORT= Postoperative radiotherapy; R=Range; RCS=Retrospective case series; RCo= Retrospective cohort; RMT=retromolar trigone; RT= Radiation Therapy; SCC= Squamous Cell Carcinoma; TORS=TransOral Robotic Surgery;

^a=Sample size=number of patients in the study with surgery and PORT for the treatment of HNSCC. This n may not be same # as overall n included in the study

Risk of bias of included studies was overall acceptably low, with the most common risk of bias being due to confounding, selection of participants into the study or analysis, and missing data (Figure S1). A funnel plot with Egger’s test (−1.3, 95%CI, −2.9 to 0.3, p=0.103; Figure S2) showed that all studies lie inside the funnel except for two with no asymmetry, suggesting little evidence of publication bias.

Care Delivery Setting and Patient Characteristics

Timely PORT was analyzed in a variety of care delivery settings and HNSCC patient populations (Tables 2–4). Studies most commonly analyzed data from a single institution (47.2%; n=17), of which n=14 were academic centers, n=2 were urban community hospitals, and n=1 as a VA medical center. Many studies (n=16; 44.4%) utilized cancer registry data from the NCDB. Thirteen (36.1%) studies included patients with all HNSCC subsites. PORT delays were also analyzed in a variety of specific HNSCC sub-populations including 11 studies (30.6%) that were subsite-specific (e.g., oral cavity), 9 (25.0%) that were treatment-specific (e.g., transoral robotic surgery), and 3 (8.3%) that analyzed a specific other sub-population (e.g., specific health insurance).

Definitions of Delay in Starting PORT

Eighty-one percent of studies (n=29/36) used a definition of PORT delay to analyze and report their data (Tables 2 and 3), while 19.4% (n=7/36) reported time-to-PORT without defining delay (Table 4).^{8–10,45–47} Of the studies that analyzed delays in starting PORT, the overwhelming majority (86.2%; n=25/29) utilized the definition in the CoC Quality Metric and NCCN Guidelines of > 6 weeks (42 days) after surgery (Table 2). Of the articles that used alternate definitions of delay, PORT delay was defined as < 42 days in two studies (> 40^48,49 days) and > 42 days in two studies (50⁵⁰, and >67⁵¹days). The studies that defined delay as 40 days utilized recursive partitioning analysis (RPA) and multivariable cubic spline functions, while the studies with 50- and 67-day definitions used RPA and cohort percentiles, respectively.

Table 3.

Characteristics of Included Studies with PORT Delay Defined as Anything Other Than >6 weeks.

Author, Year	Study Design, OLE	Data Source/Facility Type	Patient Population	Years of Diagnosis or Treatment	Sample Size, No.a	PORT Delay Definition, days	Derivation of Delay Definition	Freq of Delay, %	Time to PORT, days
HNSCC
Ho et al,49 2018	RCo, 2b	NCDB	HNSCC	2004-2013	15,131	>40	Derived (multivariable cubic spline functions)	75.6	Median 49 (IQR 40 to 62)
Ponduri and Liao,50 2021	RCo, 2b	Single Institution, urban, community-based academic center	HNSCC	2005-2017	184	>50	Derived (RPA)	46.7	Median 48.5 (IQR 41 to 67)
Tumati et al,51 2019	RCo, 2b	Multi-Institutional, 1 county hospital & 1 academic	HNSCC	2006-2014	277	>67	Descriptive (75th percentile)	25.0	Median 54 (IQR 42 to 67)
Subsite-specific
Goel et al,48 2019b	RCo, 2b	NCDB	OPSCC, AJCC 8th edition stage III-IV	2010-2014	3,550	>40	Derived (RPA)	63.0	Median 43 (IQR 35 to 55)

AJCC= American Joint Committee on Cancer; Freq= Frequency; HNSCC= head and neck squamous cell carcinoma; NCDB=National Cancer Database; IQR= Interquartile range; OLE= Oxford Level of Evidence; OPSCC= Oropharyngeal Squamous Cell Carcinoma; PORT= Postoperative radiotherapy; RCo= Retrospective cohort; RPA=Recursive partitioning analysis;

^a=Sample size=number of patients in the study with surgery and PORT for the treatment of HNSCC. This n may not be same # as overall n included in the study.

Time-to-PORT

Eleven articles reported ranges of time-to-PORT.^{16,19,22,23,45,50,52–56} The shortest PORT interval reported was 13 days¹⁶ and the longest was 369 days⁵⁰ (although NCDB studies frequently excluded patients with time-to-PORT > 180 days due to concerns about data accuracy and perceived clinical relevance). Ten studies reported mean time-to-PORT, with means ranging from 40.8 ± 9.7 days⁵⁷ to 67.8 ± 36.6 days.⁵⁸ Twenty-one studies reported median time-to-PORT, with medians ranging from 33 days⁵⁴ to 59 days.⁹

Meta-Analysis of Patient Characteristics

The mean age of patients in the meta-analysis was 58.6 years (Range 20 to 89 years; 11 studies, n=61,935 patients).^{9,16,22,23,51–54,56,57,59} Nearly three-quarters of patients (72.8%; 95% CI, 68.2% to 77.2%) were male (17 studies; n=62,451 patients), 73.3% of patients (95% CI, 64.0% to 81.6%) were white, and 15.2% (95% CI, 9.6% to 21.8%) were Black (11 studies; n=61,818 patients).

Meta-Analysis of Frequency of Delays in Starting Guideline-Adherent PORT (>6 weeks postoperatively)

Fourteen studies, comprising 61,549 patients undergoing surgery and PORT (studies ranging from n=17 to 60,776 patients), were included in the meta-analysis of frequency in delays starting PORT. The pooled frequency of PORT delay > 6 weeks was 48.6% (95% CI, 41.4% to 55.9%) (Figure 2).^{3,16,19,22,23,52–55,57–61} The pooled frequency of PORT delay was unchanged in the sensitivity meta-analysis excluding the NCDB study (pooled delay frequency = 48.0; 95% CI, 39.2% to 56.8%; Figure S3).

Figure 2.

Frequency of PORT delay (> 6 weeks) for patients with HNSCC

HNSCC= Head and neck squamous cell carcinoma; PORT= Postoperative Radiotherapy

Meta-Analysis of Time-to-PORT

Mean time-to-PORT was 47.4 days (95% CI, 43.4 to 51.4 days) in the meta-analysis of seven studies (n=61,153) (Figure 3).^{8,22,53,55,57–59} In the sensitivity meta-analysis excluding the NCDB study, mean time-to-PORT was 46.5 days (95%CI, 42.4 to 50.7 days; Figure S4). The median time-to-PORT was 45.8 days (95% CI, 42.4 to 49.3 days) in the meta-analysis of twelve articles (n=62,078).^{9,16,22,23,45,50–56} We then analyzed median time-to-PORT stratified by PORT delay (i.e., initiation of PORT ≤ 6 weeks vs > 6 weeks) among four studies where data were available to calculate both.^16,22,23,53 Among the 26,864 patients with timely initiation of PORT (≤ 6 weeks), the median time-to-PORT was 34.7 days (95% CI, 33.0 to 36.4 days). Among the 34,152 patients with delayed initiation of PORT (> 6 weeks), the median time-to-PORT was 53.9 days (95% CI, 49.9 to 57.9 days).

Figure 3.

Mean Time-to-PORT for patients with HNSCC

HNSCC= Head and Neck Squamous Cell Carcinoma; PORT= Postoperative Radiotherapy

Discussion

There are a number of important findings from our systematic review and meta-analysis describing the frequency of delays in starting PORT among patients with HNSCC. First, we demonstrated that there is a substantial literature (n=36 studies) reporting data on timely PORT for patients with HNSCC in the US since 2004 involving a variety of care delivery settings and patient populations. Second, although there is some heterogeneity, most studies define PORT delay using the 6-week cutoff concordant with the NCCN Guidelines and CoC metric. Third, nearly half of patients with HNSCC (48.6%) experience a delay in starting timely, guideline-adherent PORT.

Definition of Delay and Reporting Time-to-PORT

Our systematic review affirms the consensus around reporting delays in starting PORT as > 6 weeks following surgery while highlighting opportunities to standardize reporting. Of the articles in the systematic review, 81% defined delayed PORT and reported a frequency of delays, while 19% described time-to-PORT without defining delay. Of the studies that defined delays in starting PORT, the overwhelming majority (86.2%) utilized > 6 weeks from surgery, the definition of delay in NCCN guidelines and the CoC quality metric. This 6-week definition for PORT delay has a strong underlying radiobiologic rationale and robust association with oncologic outcomes.^3–14,62,63 In addition, two of the studies^48,49 that attempted to define optimal time-to-PORT thresholds based on the association of delays with survival derived a nearly identical definition of delay (> 40 days instead of > 42 days). Establishing consensus in defining delays in starting PORT is imperative to characterize current institutional practices, facilitate cross-institution collaboration, ensure compatibility in analyses, and assess progress improving the delivery of timely PORT.

While reporting delays in starting PORT as a dichotomous outcome relative to a 6-week threshold is helpful for standardizing across studies, reporting time-to-PORT as a continuous variable provides complementary information. Increasing length of delays beyond 6 weeks are associated with a corresponding increase in mortality up to 10-weeks after surgery.^17,34,49 As a result, reducing time-to-PORT from a median of 9 weeks postoperatively to 8 weeks after surgery would result in a clinically meaningful improvement in patient outcomes. Future research evaluating timely PORT should therefore (1) report both delays in starting PORT as a dichotomous measure and time-to-PORT as a continuous measure; and (2) define a delay in starting PORT according to the 6-week interval following surgery which has been adopted by the NCCN and CoC.

Frequency of Delays in Starting PORT

Nearly half of patients with HNSCC included in this meta-analysis experienced a delay in starting timely, guideline-adherent PORT. Timely PORT is of therapeutic significance for patients with HNSC because of its association with oncologic outcomes.⁶⁴ Within the setting of a randomized clinical trials, delays in starting guideline-adherent PORT among patients with HNSCC were associated with worse locoregional control and survival.⁴ The association of PORT delays with worse locoregional control, recurrence-free survival, and overall survival has been confirmed in three systematic reviews and two meta-analyses,^11,13,14 although this finding was not universal across individual studies.^34,65 Among those with a delay in starting PORT in the current study, the median time-to-PORT was 12 days beyond the 6 week threshold. Although 12 days beyond the 6-week threshold may seem inconsequential, delays of this magnitude are associated with increased mortality. One NCDB study identified that a delay in starting PORT of 8 weeks vs 6 weeks after surgery was associated with a 10% increase in the adjusted odds of mortality,¹⁷ while a different NCDB study suggested that each day of delay beyond 40 days was associated with a 4% increase in adjusted mortality up to 70 days.⁴⁹

Although delays in starting PORT are common, we observed significant variability across studies, with delays ranging from 28.1%⁵⁷ to 89.5%.³ Factors associated with PORT delay are critical to understand for a number of reasons. First, appropriate risk adjustment for observed and expected rates of PORT delay based on institutional case-mix is critical to ensure accurate and fair reporting. Delays in starting PORT disproportionately affect patients of Black race and Hispanic ethnicity; Medicaid or no insurance; lower levels of education, health literacy, and social support; and those with care fragmentation (usually due to rurality and/or transportation insecurity).^6,66–68 Without appropriate risk adjustment, institutions serving medically vulnerable patients could be inappropriately judged as delivering lower quality care. Second, variability in performance across institutions and patient populations highlights an opportunity to identify the sub-populations of patients at highest risk of PORT delay. These patients could be targeted by interventions to decrease delays in starting PORT. Third, further investigation into these sources of heterogeneity could enhance our understanding of the care delivery mechanisms and patient-, caregiver-, and provider behaviors that facilitate the delivery of timely, guideline-adherent PORT. To date, no study has systematically reviewed or meta-analyzed how studies evaluating PORT delay collect and analyze sociodemographic factors nor characterized how sociodemographic factors are associated with delays in starting PORT. Our findings reinforce the need for a future study that specifically focuses on understanding how sociodemographic data are collected, analyzed, and related to PORT delay.

Interventions to Decrease Delays in Starting PORT

The recent selection of initiation of PORT within 6 weeks of surgery as the first and only quality metric for HNSCC by the CoC provides a unique opportunity for institutions to improve quality of care delivery, equity, and survival for patients with HNSCC.¹ To that end, the field is beginning to shift from studies describing the high rate of PORT delay to studies evaluating interventions to improve the delivery of timely PORT.^3,55,69,70 Divi et al. showed that an intervention targeting delayed dental extractions, delayed radiation oncology consults, and inadequate patient engagement reduced the rate of delays in starting PORT from 38% to 27%.⁵⁵ Voora et al. reported that a patient navigator-based intervention to improve communication and scheduling between specialties decreased delays in starting PORT from 89% to 50% among patients undergoing free flap reconstruction.³ Graboyes et al. demonstrated a PORT delay rate of 14% in a single-arm trial evaluating a navigation-based multilevel intervention targeting patient knowledge and expectations, communication, care coordination, transportation insecurity, and referral tracking.⁶⁹ Lastly, Hudson et al. reported a PORT delay rate of 25% among patients with HNSCC after integrating clinical pathways, enhancing closed-loop communication, and improving referral tracking.⁷⁰ The interventions in these small studies highlight common themes and could form the basis of multi-disciplinary quality improvement work at other institutions.

However, as studies evaluate interventions to decrease delays starting PORT, it is also critical to measure (and ensure) that unintended downstream harms do not occur by rushing patients prematurely into adjuvant therapy. Intervention studies must therefore rigorously evaluate the effect of interventions that aim to enhance delivery of timely PORT on outcomes such as radiation treatment breaks, late flap failure, radiation necrosis, patient satisfaction, and ultimately oncologic outcomes like recurrence and survival.

Institutional Performance on the CoC Quality Metric

While rigorous research is needed to reduce the rate of PORT delays, it is also critical to understand the context surrounding the current CoC metric. The CoC metric for delays in starting PORT for patients with HNSCC is exploratory (i.e., data are collected, but institutional performance on the metric is not tied to accreditation).⁷¹ Second, the metric only applies to SCC of the oral cavity, oropharynx, hypopharynx, and larynx and not to other histologies or sites (salivary gland, skin, etc.).⁷¹ Third, risk-adjusted targets for institutional performance have not yet been defined.⁷¹ Findings from the small intervention studies to improve timely PORT suggest that achieving 100% adherence in the delivery of timely, guideline-adherent PORT for patients with HNSCC is not realistic. Divi et al. reported that unavoidable delays starting PORT occurred in 18% of patients after the intervention,⁵⁵ Voora et al. excluded 20% of their study sample for reasons that would result in unavoidable delays starting PORT, and Graboyes et al. reported an overall PORT delay rate of 14%. An institutional target performance of 80%, for example, would appear feasible based on the limited intervention studies to date and align with data-driven and feasible institutional targets for other quality metrics in HNSCC such as lymph node yield and margin-negative surgery.⁷² Future work will be necessary to identify targets for PORT delay that drive improvements in quality while remaining feasible.

Limitations

This systematic review and meta-analysis has multiple strengths including its use of pooled data about timely PORT delivery from different study designs, practice settings, and patient populations to characterize timely PORT delivery in depth. Additionally, we established clearly defined eligibility criteria for the patients included in this study based on clinical relevance, contacted authors for missing or unclear data which obviated the requirement to exclude studies due to incomplete data, and utilized a rigorous meta-analytic methodology while avoiding duplication of NCDB studies. However, there are several important limitations. There is a chance that publication bias affected our findings. Researchers who sought to determine institutional frequency of PORT delay and found higher than expected rates of delay and/or longer times to PORT initiation might be less encouraged to publish their findings (as opposed to those with low rates of delay). This could lead to our results under-estimating the frequency of PORT delay and time-to-PORT. However, the included articles reported a wide range of PORT delay frequency and time-to-PORT. There is also potential for duplication of patients whose data are represented in institutional studies and again in the NCDB (or multiple NCDB studies with nearly identical patient eligibility criteria and years of study). We attempted to address this potential limitation by (1) including one study that utilized the NCDB in each meta-analysis and (2) performing sensitivity analyses excluding the NCDB study. Finally, as described in the discussion, we do not evaluate how sociodemographic factors are collected and analyzed nor how they are associated with PORT delay, as this is outside the scope of this current study. However, future research is necessary to focus specifically on addressing these important questions.

Conclusion

In this systematic review and meta-analysis, we demonstrated that approximately one-half of patients with HNSCC fail to start PORT in a timely manner relative to NCCN Guidelines and the CoC quality metric. Collectively, this systematic characterization surrounding timely initiation of PORT for patients with HNSCC affirms consensus definitions of PORT delay while highlighting opportunities to standardize reporting, provides national benchmarks for PORT delay against which institutions can measure progress, and highlights opportunities and potential strategies to enhance the quality of care for patients with HNSCC.

Supplementary Material

Fig S2

Figure S2. Egger’s regression test—publication bias^43,44

Fig S1

Figure S1. Risk of Bias of Included Studies (ROBINS-E)³²

Fig S4

Figure S4. Mean Time-to-PORT for Patients with HNSCC, Excluding 1 NCDB study.

Fig S3

Figure S3. PORT Delay (>6 weeks) Frequency in Patients with HNSCC, Excluding 1 NCDB study

Appendix A. Search Strategy

PubMed (U.S. National Library of Medicine, National Institutes of Health) search strategy:

((“Head and Neck Neoplasms”[Majr:NoExp] OR “Squamous Cell Carcinoma of Head and Neck”[Majr] OR “Laryngeal Neoplasms”[Mesh] OR “Mouth Neoplasms”[Mesh] OR “Nose Neoplasms”[Mesh] OR “Oropharyngeal Neoplasms”[Mesh] OR “Paranasal Sinus Neoplasms”[Mesh] OR “Pharyngeal Neoplasms”[Mesh] OR “Tongue Neoplasms”[Mesh] OR HNSCC[tiab] OR “head and neck”[tiab] OR “head & neck”[tiab]) OR ((hypopharyngeal[tiab] OR laryngeal[tiab] OR mouth[tiab] OR nose[tiab] OR oral[tiab] OR oropharyngeal[tiab] OR paranasal[tiab] OR pharyngeal[tiab] OR salivary[tiab] OR tongue[tiab]) AND (cancer*[tiab] OR neoplasm*[tiab] OR carcinoma*[tiab])) AND (“Radiotherapy, Adjuvant”[Majr] OR “adjuvant radiotherapy”[tiab] OR “Chemoradiotherapy, Adjuvant”[Majr] OR “adjuvant chemoradiotherapy”[tiab] OR “adjuvant radiation”[tiab] OR “adjuvant therapy”[tiab] OR “postoperative radiotherapy”[tiab] OR “post operative radiotherapy”[tiab] OR “post-operative radiation”[tiab] OR “post-operative radiotherapy”[tiab] OR “postoperative radiation”[tiab] OR “postoperatively irradiated”[tiab] OR PORT[ti] OR “radiation interval”[tiab] OR “surgery to adjuvant”[tiab] OR “surgery-to-radiation”[tiab] OR “surgery-to-radiotherapy”[tiab] OR “surgery-to-RT”[tiab]) AND (delay*[tiab] OR “delayed PORT”[tiab] OR “radiation interval”[tiab] OR “Time Factors”[MeSH] OR “Time-to-Treatment”[MeSH] OR time*[ti] OR timing[ti] OR “time to adjuvant”[tiab] OR TS-SR[tiab] OR TS-RT[tiab] OR “total treatment package”[tiab] OR “treatment package time”[tiab] OR “6 weeks”[tiab])) NOT (“Animals”[Mesh] NOT “Humans”[Mesh])

• Filters/limits: English

• Updated December 2, 2022

  • Updated # of records: 616 results (PMDs 30737961 and 34333218 not captured)

• Date searched: October 10, 2022

• # of records identified: 395

• Librarian peer-reviewer: Christine Andresen

• Date of peer-review: September 30, 2022

CINAHL Complete (EBSCOhost) search strategy:

(MH “Head and Neck Neoplasms” OR MH “Squamous Cell Carcinoma of Head and Neck” OR “head and neck” OR “head & neck” OR HNSCC OR hypopharyngeal cancer* OR hypopharyngeal carcinoma* OR hypopharyngeal neoplasm* OR MH “Laryngeal Neoplasms” OR laryngeal cancer* OR laryngeal carcinoma* OR laryngeal neoplasm* OR MH “Mouth Neoplasms+” OR mouth cancer* OR mouth carcinoma* OR mouth neoplasm* OR MH “Nose Neoplasms+” OR nose cancer* OR nose carcinoma* OR nose neoplasm* OR oral cancer* OR oral carcinoma* OR oral neoplasm* OR oropharyngeal cancer* OR oropharyngeal carcinoma* OR oropharyngeal neoplasm* OR MH “Paranasal Sinus Neoplasms” OR paranasal cancer* OR paranasal carcinoma* OR paranasal neoplasm* OR MH “Pharyngeal Neoplasms+” OR pharyngeal cancer* OR pharyngeal carcinoma* OR pharyngeal neoplasm* OR salivary cancer* OR salivary carcinoma* OR salivary neoplasm* OR MH “Tongue Neoplasms” OR tongue cancer* OR tongue carcinoma* OR tongue neoplasm*) AND (MM “Radiotherapy, Adjuvant” OR “adjuvant radiotherapy” OR MM “Chemoradiotherapy, Adjuvant” OR “adjuvant chemoradiotherapy” OR “adjuvant radiation” OR “adjuvant therapy” OR “postoperative radiotherapy” OR “post-operative radiotherapy” OR “postoperative radiation” OR “postoperative radiation” OR “postoperatively irradiated” OR TI PORT OR “radiation interval” OR “surgery to adjuvant” OR “surgery-to-radiation” OR “surgery-to-radiotherapy” OR “surgery-to-RT”) AND (delay* OR “delayed PORT” OR “radiation interval” OR MH “Time Factors” OR TI time* OR TI timing OR “time to adjuvant” OR TS-SR OR TS-RT OR “total treatment package” OR “treatment package time” OR “6 weeks”)

• Filters/limits: English

• Updated December 2, 2022

  • Updated # of records: 135 results

• Date searched: October 10, 2022

• # of records identified: 96

• Librarian peer-reviewer: Christine Andresen

• Date of peer-review: September 30, 2022

Scopus (Elsevier) search strategy (basic search):

#1: TITLE: {head and neck} OR {head & neck} OR HNSCC OR “hypopharyngeal cancer” OR “hypopharyngeal carcinoma” OR “hypopharyngeal neoplasm” OR “laryngeal cancer” OR “laryngeal carcinoma” OR “laryngeal neoplasm” OR “mouth cancer” OR “mouth carcinoma” OR “mouth neoplasm” OR “nose cancer” OR “nose carcinoma” OR “nose neoplasm” OR “oral cancer” OR “oral carcinoma” OR “oral neoplasm” OR “oropharyngeal cancer” OR “oropharyngeal carcinoma” OR “oropharyngeal neoplasm” OR “paranasal cancer” OR “paranasal carcinoma” OR “paranasal neoplasm” OR “pharyngeal cancer” OR “pharyngeal carcinoma” OR “pharyngeal neoplasm” OR “salivary cancer” OR “salivary carcinoma” OR “salivary neoplasm” OR “tongue cancer” OR “tongue carcinoma” OR “tongue neoplasm” #2: ABSTRACT: {head and neck} OR {head & neck} OR HNSCC OR “hypopharyngeal cancer” OR “hypopharyngeal carcinoma” OR “hypopharyngeal neoplasm” OR “laryngeal cancer” OR “laryngeal carcinoma” OR “laryngeal neoplasm” OR “mouth cancer” OR “mouth carcinoma” OR “mouth neoplasm” OR “nose cancer” OR “nose carcinoma” OR “nose neoplasm” OR “oral cancer” OR “oral carcinoma” OR “oral neoplasm” OR “oropharyngeal cancer” OR “oropharyngeal carcinoma” OR “oropharyngeal neoplasm” OR “paranasal cancer” OR “paranasal carcinoma” OR “paranasal neoplasm” OR “pharyngeal cancer” OR “pharyngeal carcinoma” OR “pharyngeal neoplasm” OR “salivary cancer” OR “salivary carcinoma” OR “salivary neoplasm” OR “tongue cancer” OR “tongue carcinoma” OR “tongue neoplasm”

#3: #1 OR #2

AND

#4: TITLE: PORT OR {adjuvant radiotherapy} OR {adjuvant chemoradiotherapy} OR {adjuvant radiation} OR {adjuvant therapy} OR {postoperative radiotherapy} OR {post-operative radiation} OR {postoperatively irradiated} OR {radiation interval} OR {surgery to adjuvant} OR {surgery-to-radiation} OR {surgery-to-radiotherapy} OR {surgery-to-RT}

#5: ABSTRACT: {adjuvant radiotherapy} OR {adjuvant chemoradiotherapy} OR {adjuvant radiation} OR {adjuvant therapy} OR {postoperative radiotherapy} OR {post-operative radiation} OR {postoperatively irradiated} OR {radiation interval} OR {surgery to adjuvant} OR {surgery-to-radiation} OR {surgery-to-radiotherapy} OR {surgery-to-RT}

#6: #4 OR #5

AND

#7: TITLE: delay* OR {delayed PORT} OR {radiation interval} OR time* OR timing OR {time to adjuvant} OR TS-SR OR TS-RT OR {total treatment package} OR {treatment package time} OR {6 weeks}

#8: ABSTRACT: delay* OR {delayed PORT} OR {radiation interval} OR {time to adjuvant} OR TS-SR OR TS-RT OR {total treatment package} OR {treatment package time} OR {6 weeks}

#9: #7 OR #8

#10: #3 AND #6 AND #9

• Filters/limits: English

• Updated search December 2, 2022

  • Updated # of records: 176 results

• Date searched: October 10, 2022

• # of records identified: 99

• Librarian peer-reviewer: Christine Andresen

• Date of peer-review: September 30, 2022

Scopus (Elsevier) search strategy (advanced document search):

( ( TITLE ( {head and neck} OR {head & neck} OR hnscc OR “hypopharyngeal cancer” OR “hypopharyngeal carcinoma” OR “hypopharyngeal neoplasm” OR “laryngeal cancer” OR “laryngeal carcinoma” OR “laryngeal neoplasm” OR “mouth cancer” OR “mouth carcinoma” OR “mouth neoplasm” OR “nose cancer” OR “nose carcinoma” OR “nose neoplasm” OR “oral cancer” OR “oral carcinoma” OR “oral neoplasm” OR “oropharyngeal cancer” OR “oropharyngeal carcinoma” OR “oropharyngeal neoplasm” OR “paranasal cancer” OR “paranasal carcinoma” OR “paranasal neoplasm” OR “pharyngeal cancer” OR “pharyngeal carcinoma” OR “pharyngeal neoplasm” OR “salivary cancer” OR “salivary carcinoma” OR “salivary neoplasm” OR “tongue cancer” OR “tongue carcinoma” OR “tongue neoplasm” ) ) OR ( ABS ( {head and neck} OR {head & neck} OR hnscc OR “hypopharyngeal cancer” OR “hypopharyngeal carcinoma” OR “hypopharyngeal neoplasm” OR “laryngeal cancer” OR “laryngeal carcinoma” OR “laryngeal neoplasm” OR “mouth cancer” OR “mouth carcinoma” OR “mouth neoplasm” OR “nose cancer” OR “nose carcinoma” OR “nose neoplasm” OR “oral cancer” OR “oral carcinoma” OR “oral neoplasm” OR “oropharyngeal cancer” OR “oropharyngeal carcinoma” OR “oropharyngeal neoplasm” OR “paranasal cancer” OR “paranasal carcinoma” OR “paranasal neoplasm” OR “pharyngeal cancer” OR “pharyngeal carcinoma” OR “pharyngeal neoplasm” OR “salivary cancer” OR “salivary carcinoma” OR “salivary neoplasm” OR “tongue cancer” OR “tongue carcinoma” OR “tongue neoplasm” ) ) ) AND ( ( TITLE ( port OR {adjuvant radiotherapy} OR {adjuvant chemoradiotherapy} OR {adjuvant radiation} OR {adjuvant therapy} OR {postoperative radiotherapy} OR {post-operative radiation} OR {postoperatively irradiated} OR {radiation interval} OR {surgery to adjuvant} OR {surgery-to-radiation} OR {surgery-to-radiotherapy} OR {surgery-to-RT} ) ) OR ( ABS ( {adjuvant radiotherapy} OR {adjuvant chemoradiotherapy} OR {adjuvant radiation} OR {adjuvant therapy} OR {postoperative radiotherapy} OR {post-operative radiation} OR {postoperatively irradiated} OR {radiation interval} OR {surgery to adjuvant} OR {surgery-to-radiation} OR {surgery-to-radiotherapy} OR {surgery-to-RT} ) ) ) AND ( ( TITLE ( delay* OR {delayed PORT} OR {radiation interval} OR time* OR timing OR {time to adjuvant} OR ts-sr OR ts-rt OR {total treatment package} OR {treatment package time} OR {6 weeks} ) ) OR ( ABS ( delay* OR {delayed PORT} OR {radiation interval} OR {time to adjuvant} OR ts-sr OR ts-rt OR {total treatment package} OR {treatment package time} OR {6 weeks} ) ) ) AND ( LIMIT-TO ( LANGUAGE, “English” ) )