Abstract
Introduction
Recurrent head and neck cancer (HNC) after radiotherapy presents a reconstructive challenge. Whether pedicled or free flap reconstruction leads to better outcomes remains unclear. This review aims to assess the outcomes of pedicled and free flap reconstruction in patients with recurrent HNC after radiotherapy.
Method
The protocol was developed prospectively, peer-reviewed and registered on the PROSPERO database. A search strategy was designed and conducted across multiple databases, including MEDLINE and Embase (1990–2024). Additional sources included hand searches, citation searches, and clinical trial registers. 9233 titles and abstracts were screened, full-text of 422 reports reviewed, and 27 cohort studies included. Quality assessment was performed using standardised risk of bias tools.
Results
27 cohort studies, representing a total of 6879 participants and 5919 flaps, were included. All studies included patients who underwent flap reconstruction for salvage of recurrent HNC following radiotherapy. Included study designs precluded a direct comparative analysis of differences between flap types. Reporting of patient-relevant outcomes such as swallowing or quality of life was poor. For free flaps, total flap loss ranged from 0 to 29 % and partial flap loss ranged from 0 to 14.7 %. The certainty of the evidence was judged to be very low.
Conclusions
Reconstruction for recurrent HNC after radiotherapy can be achieved with consistency using pedicled or free flaps. A direct comparison cannot be made with available data. The heterogeneity in study designs and lack of comprehensive or patient-relevant outcome reporting underscore the evidence gap and need for well-designed studies to better inform clinical decision-making.
Keywords: Flap, Aerodigestive cancer, Head and neck cancer, Recurrent cancer, Salvage surgery, Radiotherapy
Introduction
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and associated with risk factors including smoking, alcohol consumption, tobacco chewing and Human Papilloma Virus.1 Radiotherapy, with or without concurrent chemotherapy or surgery, is an established primary treatment for HNSCC across various subsites and stages.2 However, about half of patients with HNSCC have recurrence or metastatic disease.1 Recurrent HNSCC after radiotherapy generally have a poor prognosis in terms of quality of life and life expectancy. Salvage surgery is considered a last-resort but most optimal treatment for recurrent disease which require oncologic resection, often resulting in complex defects that necessitate reconstruction using either free or pedicled flaps.
Because the surgical field has already been subjected to radiotherapy, it is likely to be vessel-deplete and heavily fibrosed, making surgical reconstruction challenging.3, 4, 5, 6 A systematic review and meta-analysis found that flaps for head and neck performed in irradiated fields had significantly greater risk ratios for flap failure, complications, reoperation and fistula compared to flaps performed in non-irradiated fields.5 Reconstructive failure can significantly impact short-term prognosis and survival.7 Pedicled flaps may be undertaken to minimise anaesthetic time and the perceived higher risk of flap, and thus reconstructive, failure. By contrast, free flaps are more complex but offer more tailored reconstructions and hence potentially superior outcomes in terms of form and function. The indications for pedicled versus free flaps for salvage of recurrent HNSCC after radiotherapy are ill-defined and published data on the success rates are limited.
An analysis of the outcomes of flap reconstruction including a comparison of free and pedicled flap options can support evidence-based clinical decision-making for patients requiring salvage flap reconstruction for recurrent HNSCC. The aim of this systematic review is to provide the most up-to-date evidence synthesis and assess the outcomes of pedicled and free flap reconstructions for patients with recurrent HNSCC after radiotherapy.
Methods
This review followed the Cochrane Handbook for Systematic Reviews of Interventions and was reported in accordance with the PRISMA statement and checklist. The protocol was developed prospectively, locally peer-reviewed and registered in the PROSPERO database (CRD42020132323).
A comprehensive search strategy was developed with medical library support and applied to the following bibliographic databases using the Ovid interface: MEDLINE (1946-present) and EMBASE (1974-present) on March 2021 and an update search was performed in April 2024 (Appendix A). Trial registers including ClinicalTrials.gov (www.clinicaltrials.gov) and the UK National Institute for Health Research Website (https://bepartofresearch.nihr.ac.uk/), and OpenGrey (www.opengrey.eu) and the Grey Literature Report (https://www.greylit.org/) were also searched. No date or language limits were applied. Both free text and medical index searches were performed, then combined.
Search results were merged and deduplicated prior to screening using Rayyan. Abstracts were screened in duplicate (MS, AB, AK). Full texts were screened in duplicate based on predefined criteria. Additional bibliographic screening was performed. Disagreements were resolved by discussion with a fourth author (JC).
Search strategy
Articles published until 21st January 2024 were used with no date or language restrictions applied. Both MeSH and free-text search terms were developed using the Population, Intervention, Comparison, Outcome (PICO) approach for clinical questions, and combined using Boolean operators (Appendix 1) (Searches undertaken in 16th April 2020 and updated 21st January 2024). The full search strategy is available on the PROSPERO database (CRD42020132323)
Selection criteria
The study inclusion criteria were determined at the protocol stage.
PICO format was employed as follows:
-
Participants:
Patients of any age with recurrence of advanced stage head and neck squamous cell carcinoma (HNSCC) following primary (definitive) radiotherapy (RT) with or without concurrent chemotherapy (CRT) and in whom, as part of secondary treatment, underwent either pedicled or free flap reconstruction.
-
Intervention:
oncologic resection and reconstruction
-
Comparator:
pedicled versus free flap reconstruction
Outcomes:
-
Primary outcomes:
health-related quality of life outcomes
-
Secondary outcomes:
overall survival, disease-free survival, locoregional control, adverse events (including flap survival, further operations, fistulation, wound breakdown, wound infection, thromboembolic events) and duration of hospital stay
Types of study included were experimental studies (randomised controlled trials (RCTs) and quasi-RCTs); observational studies (retrospective cohort studies with at least 10 cases (comparative and non-comparative), prospective cohort studies (comparative and non-comparative), case-control studies, case series); articles published in full until April 2020; without language limitation. Exclusion criteria included literature reviews; case reports; case series and case-control studies with fewer than 10 cases; experimental animal studies and cadaveric studies.
Exclusion criteria included treatment of a second primary cancer (i.e. no recurrent HNSCC), cancers that were not primarily aerodigestive HNSCC, recurrence of HNSCC not primarily treated with radio ± chemotherapy and patients who did not have flap reconstruction.
Given there may be different regimes of radio ± chemotherapy for primary cancer treatment at different units, we adopted a pragmatic approach and did not exclude studies based on the details of treatment regimes.
The primary focus of this review is on quality of life and functional recovery. However, we also included other relevant outcomes including survival and adverse events.
Study selection
Three review authors (MS, AB, and AK) independently screened the titles and abstracts of citations retrieved from the searches for relevance. Full text articles of potentially relevant studies were then read to construct the final selection of articles (Table 1). Any conflict between the two screening authors were moderated by a fourth author (JC) before the final decision was made. For studies where eligibility for inclusion was uncertain, we contacted the authors requesting further information. Studies were excluded in cases where no response was received after two weeks.
Table 1.
Study characteristics.
| Study | Year | Country | Study design | Funding | Intervention studied | Total cases (n = 6879) | Total relevant cases (%)a (n = 2569) | Total number of flaps (n = 5919) | Sex M:F |
Mean age in years (range) | Mean follow-up in months (range) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Horn et al.20 | 2020 | Germany | Prospective cohort | No | Free-flap reconstruction for radio-recurrent HNSCC | 28 | 28 (100) | 29 | 16:12b | 66.5 (46.5–86) b | 13.2b,c |
| Mohamed et al.25 | 2023 | USA | Retrospective cohort | No | Salvage surgery, with or without free-flap reconstruction, with post-operative adjuvant IMRT for radio-recurrent HNSCC | 55 | 31 (56) | 31 | 43:12b | 23 (27–84)q, 32 (35–82)r | 22 (1–105) b |
| Hafström et al.16 | 2023 | Sweden | Retrospective cohort | Yes | Free-flap reconstruction, for persistent, second primary or recurrent HNSCC | 83 | 61 (80.7) | 83 | 46:37b | 67c (31–87)b | 127 (49–254)b |
| Hirano et al.19 | 2023 | Japan | Retrospective cohort | Not disclosed | Free-flap reconstruction for any radio-recurrent HNSCC | 41 | 41 (100 %) | 41 | 33:8b | 63.7 (41–76)b | NR |
| Sharma et al.34 | 2022 | USA | Retrospective cohort | Yes | Salvage surgery, with or without free flap reconstruction, for recurrent HNSCC | 108 | <59 (<54.6) | 59 | 71:37b | 61.6d (25–92)b | 17.9d (0.06–198) b |
| D’Andrea et al.13 | 2022 | France | Retrospective cohort | No | Robotic-assisted salvage surgery, with or without pedicled flap or free-flap reconstruction, for radio-recurrent HNSCC or second primary within irradiated tissue | 53 | 48 (90.6) | 48 | 42:11b | 64.3d (37–87)b | 22.2d |
| Noothanapati et al.28 | 2022 | India | Retrospective cohort | No | Pedicled or free-flap reconstruction for any second primary or recurrent head and neck cancer | 193 | <193 (<100) | 193 | 149:44b | 61.4°, 54.6p | 6b |
| Pazdrowsk et al.30 | 2022 | Poland | Retrospective cohort | Not disclosed | Pedicled or free-flap reconstruction for any recurrent head and neck cancer | 100 | <68 (<68) | 100 | 62:38b | 59.6d (30–86)b | NR |
| Meulemans et al.24 | 2021 | Belgium | Retrospective cohort | Yes | Salvage total laryngectomy, with or without pedicled flap or free-flap reconstruction, for any residual, recurrent or second primary HNSCC | 405 | 231 (57.03) | 331 | 378:27b | 65.3 (40–91)b | 99.4b |
| Shankhdhar et al.33 | 2021 | India | Retrospective cohort | No | Free-flap reconstruction for any head and neck cancer, or osteoradionecrosis, within a previously irradiated or operated neck | 371 | <184 (<49.6) | 271 | 315:56b | 55c (18–85)b | NR |
| Chen et al.11 | 2021 | Taiwan | Retrospective cohort | Yes | Free-flap reconstruction for any primary or recurrent head and neck cancer | 1770 | 370 (20.9) | 1791 | 595:30n | 57n | NR |
| Moratin et al.27 | 2021 | Germany | Retrospective cohort | Not disclosed | Second, or more, free-flap reconstruction for any indication, including any primary or recurrent head and neck cancer, osteonecrosis, osteomyelitis, etc | 189 | <79 (<36 %) | 220 | 120:69b | 60 (16–92)b | NR |
| Moltedo et al.26 | 2020 | Taiwan | Retrospective cohort | Yes | Free-flap reconstruction for any primary or recurrent head and neck cancer | 1604 | 511 (31.9) | 1604 | 1531:73b | 54l, 57m | NR |
| Okamoto et al.29 | 2020 | Japan | Retrospective cohort | No | Salvage total laryngectomy, with or without free-flap reconstruction, for any recurrent head and neck cancer | 59 | 22 (37 %) | 22 | 20:2k | 73.2k | NR |
| Chen et al.12 | 2021 | China | Retrospective cohort | Yes | Pedicled flap reconstruction for any recurrent nasopharyngeal SCC or radiation-induced sarcoma of the head and neck | 52 | 36 (69.2) | 52 | 28:8i | 52.7 (31–67)j | 18.7 (6–31)j |
| Piazza et al.31 | 2020 | Italy | Retrospective cohort | No | Salvage total laryngectomy with free-flap reconstruction for radio-recurrent HNSCC | 55 | 55 (100) | 55 | 49:6 | 66 (35–85) | 6 |
| Kim et al.22 | 2020 | South Korea | Retrospective cohort | No | Free-flap reconstruction for any recurrent head and neck cancer | 116 | 89 (71.8) | 125 | 94:30b | 56.6 (24–86)b | NR |
| Banaszewski et al.9 | 2019 | Poland | Retrospective cohort | No | Free-flap reconstruction for primary and recurrent HNSCC | 100 | 45 (45.0) | 100 | 77:23b | 57.5 (27–75)b | (12–48)b |
| Chen et al.10 | 2019 | USA | Retrospective cohort | Yes | Free-flap reconstruction following glossectomy for primary and recurrent head and neck cancer | 200 | 64 (31.5) | 200 | 138:62b | 59.5b | 13.8 (7–28)b |
| Han et al.18 | 2019 | USA | Retrospective cohort |
No | Free-flap reconstruction for any primary or recurrent head and neck cancer | 48 | 17 (35.4) | 48 | 29:19b | 56 (29–92)b | 27.3 (1–205)b |
| Hamoir et al.17 | 2017 | Belgium | Retrospective cohort |
No | Pedicled or free-flap reconstruction for recurrent HNSCC | 109 | <57 (<52.3) | 57 | 82:27b | 57c (40–84)b | 30 (1–198)b |
| Anicin et al.8 | 2015 | Slovenia | Retrospective cohort | No | Pedicled flap reconstruction for primary or recurrent HNSCC | 39 | 19 (48.7) | 39 | 19:1i | 61 (52–76)i | 20.4 (2–101)b |
| Gordin et al.15 | 2014 | USA | Retrospective cohort |
No | Free-flap reconstruction for primary and recurrent HNSCC | 48 | 24 (50) | 50 | 31:17b | 57.8 (32–74)g 60.2 (36–77)h |
>6b,e |
| Llorente et al.23 | 2014 | Spain | Retrospective cohort |
No | Free-flap reconstruction for any primary or recurrent head and neck cancer | 246 | <119 (<48.3) | 259 | 206:40b | 58 (21–84)b | 36 (6–337)b |
| Kano et al.21 | 2013 | Japan | Retrospective cohort |
No | Salvage surgery, with or without free flap reconstruction, for any recurrent head and neck cancer | 486 | 10 (2.1) | 10 | 10:0f | 54 (42–75)f | 52.8 (4–71)b |
| Esteller et al.14 | 2011 | Spain | Retrospective cohort |
No | Salvage surgery, with or without pedicled or free-flap reconstruction, for recurrent HNSCC | 216 | 18 (8.3) | 21 | 30:2b,c | 55.8d (38–78)b | >24b,e |
| Righini et al.32 | 2011 | France | Retrospective cohort |
No | Salvage surgery, with or without pedicled flap reconstruction, for recurrent HNSCC | 105 | 90 (85.7) | 90 | 93:12b | 59b | 44b |
M, male; F, female; HNSCC, head and neck squamous cell carcinoma; USA, United States of America; NR, not recorded; SCC, squamous cell carcinoma; IMRT, intensity-modulated radiation therapy; ALT flap, anterolateral thigh flap; AMT flap, anteromedial thigh flap.
Patients with recurrence of advanced stage head and neck squamous cell carcinoma (HNSCC) following primary radiotherapy, with or without chemotherapy and/or surgery, and in whom, as part of their secondary (salvage) treatment, underwent either pedicled or free flap reconstruction.
Pooled data.
M:F ratio for patients with radio-recurrent HNSCC who underwent salvage surgery.
Median.
Minimum follow-up.
M:F ratio and mean age (range) for patients with radio-recurrent HNSCC who underwent free flap reconstruction as part of their secondary treatment.
Mean age (range) for males.
Mean age (range) for females.
M:F ratio and median age (range) for patients who underwent salvage surgery.
M:F ratio, mean age (range) and median length of follow-up (range) for patients with advanced recurrent nasopharyngeal SCC.
M:F ratio and mean age for patients with recurrent laryngeal cancer group who underwent pedicled flap reconstruction.
Median age for patients who underwent ALT flap reconstruction.
Median age patients who underwent AMT flap reconstruction.
Gender ratio and median age for patients with recurrent head and neck cancer.
Mean age for patients who underwent pedicled or local flap reconstruction.
Mean age for patients who underwent free-flap reconstruction.
Median age (range) at re-irradiation for patients with no locoregional recurrence following re-irradiation.
Median age (range) at re-irradiation for patients with locoregional recurrence following re-irradiation.
Data extraction
Details of eligible studies were extracted and summarised using a predefined data extraction sheet by review authors MS, AB, AK and JC, piloted independently. Data collected included study data, patient demographics, disease-specific intervention and outcome data.
Unit of analysis issues
We expected that the participant would be the unit of analysis in most of the studies. Studies may have included some participants with more than one flap. Some reported outcome data at the participant level as well as the flap level. For analysis of flap outcomes such as flap survival, we used flap level data but also mention number of participants, but for quality of life and functional outcome data, participant level data were reported. These are clearly indicated in the Results section. Given the limited studies in the review, we did not perform sensitivity analysis to investigate this decision.
Incomplete data
We anticipated several types of missing data including unreported data, participants who withdrew or dropped out and missing statistics. If the included studies did not report data, we attempted to contact the study authors to request information.
Quality assurance
Assessment of risk of bias in included studies was performed independently by review authors MS, AB and AK using the National Institute of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Each study was given an overall quality rating and disagreements were resolved by consulting a fourth author (JC).
Data analysis and synthesis
We performed simple descriptive statistics for patient demographics. As there were no comparative studies, a meta-analysis was not performed. Instead, we undertook a narrative synthesis to summarise the identified surgical and patient-related outcomes. Where possible and appropriate, pooled rates were calculated for outcomes described by three or more studies to provide overall descriptive estimates of effects of surgery and adverse events.
For studies that reported data on patients who did not meet the inclusion criteria of participants (primary cancer site and primary cancer treatment), we extracted and analysed data from the subgroup of participants in each study wherever possible.
Results
After removal of duplicates from the search results, we screened 9233 titles and abstracts from the following databases: EMBASE, MEDLINE and Cochrane Library. We also screened references of papers identified from searches.
The search identified a total of 422 reports for potential inclusion, for which we obtained full reports. Upon further inspection, we excluded 395 studies (219 wrong population; 190 wrong study design) and selected 27 studies for inclusion in the review. We found no eligible ongoing studies in our search of clinical trials registers. A flow diagram summarising the study selection process is shown in Fig. 1.
Fig. 1.
PRISMA flow diagram showing study selection for a systematic review of reconstruction in recurrent head and neck squamous cell carcinoma following radiotherapy.
Included studies
A total of 27 studies, representing a total of 6879 participants, of which <2569 were relevant for this review, were included.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 We found no randomised, quasi-randomised, or cluster-randomised studies. All 27 included studies were single-centre cohort studies, conducted in 15 countries. 26 were retrospective and 1 was prospective. Seven studies were supported by grants,10, 11, 12,16,24,26,34 while funding sources were not reported in three studies.19,27,30 No conflicts of interest were disclosed.
All studies included patients who underwent salvage surgery including flap reconstruction for recurrent HNSCC following radiotherapy. No study was designed specifically to compare outcomes of pedicled versus free flap reconstruction in patients with recurrent HNSCC following radiotherapy who underwent salvage surgery. 17 studies investigated free flaps only, 4 pedicled flaps only and 5 both. Only two studies allowed direct analysis of differences between pedicled and free flap reconstruction as part of salvage surgery in recurrent HNSCC but this also included patients who did not have radiorecurrent HNSCC.28,30 However, these were both subject to selection bias as the allocation to the pedicled and free flap groups were not randomised. Only 5 studies used patient reported outcome measures such as quality of life and function e.g. swallowing. Only 17 studies reported any oncological outcome data (overall / disease-free survival, locoregional control).
Apart from the essential detail of the intervention in the study reports, it was not always possible to ascertain the additional detail about the defect (e.g. size, location, availability of recipient vessels) or management steps (e.g. radiotherapy regimen).
Most studies reported flap survival data. However, study authors did not always clearly report patient-reported outcomes, patient survival rates and adverse events. Timing of outcome assessment was not always clear.
It was not always possible to extract the relevant data from the study design due to incomplete reporting of data. See Appendix 2.
Risk of bias analysis
We have summarised the risk of bias judgements for the individual trials in Fig. 2. In our risk of bias analysis, we found that out of the 27 studies included. All studies had clearly specified research questions and population. All studies reported participation rates, but none of the studies had blinded outcome assessors. Additionally, there were no studies with follow-up losses less than or equal to 20 %. Only 6 studies measured key confounding variables.
Fig. 2.
Summary of the risk of bias judgements for individual studies.
Effects of interventions
We report the results for the included studies. Findings are also reported in Table 2: Summary of Findings 1 and Table 3: Summary of Findings 2. We did not conduct subgroup analyses or sensitivity analyses because there were insufficient studies and data was insufficiently granular.
Table 2.
Summary of findings–survival, function and patient reported outcome measures (PROMs).
| Disease Control |
||||||
|---|---|---|---|---|---|---|
| Study | Patient reported and functional outcomes used | Outcomes | Overall survival | Disease free survival | Locoregional ctrl | Mean hospital stay (days, unless stated otherwise) |
| Horn et al.20 | Quality of life after 12 months: EORTC questionnaire QLQ-C30 and QLQ-H&N35 | All: global QoL, role and emotional functioning decreased at 3/12 post salvage surgery but recovers to baseline at 12 months; physical functioning did not reach baseline at 12 months. QLQ-H&N35: significant reduction in pain at 3 months and 1 year. Swallowing and speech items at baseline at 12 months | 100 % during hospital stay | 1 year 68.4 %, 2 years 59.3 % | Progression free 38.5 % (1 year), 23.1 % 2 years | 19.5 |
| Mohamed et al.25 | NR | NR | NR | NR | All: 42 % had locoregional recurrence with a median time to recurrence of 5 months (range 1–16). | NR |
| Hafström et al.16 | NR | NR | All: Local recurrence group - 2-year OS: 67.2, 5-year OS: 39.3. Loco-regional recurrent group - 2-year OS: 9.1, 5-year OS: 4.5 | All: Median 26 months [95 % CI 11.7–40.3], 52.6 ± 5.6 % at 2 years, 41.9 ± 5.8 % at 5 years, 35.6 ± 5.9 % at 10 years | NR | NR |
| Hirano et al.19 | NR | NR | 100 % | NR | Not documented | NR |
| Sharma et al.34 | NR | NR | NR | pooled: 2- and 5-year DFS 26.3 % and 12.6 % | NR | NR |
| D’Andrea et al.13 | MD Anderson Dysphagia Inventory, EORTC QLQC-30, EORTC QLQ-H&N35. | All: MDADI total score no meaningful change at 1 and 2 years; QLQ-C30 global score improved at 2 years. All symptoms scales decreased at 2-year timepoints showing an improvement in QoL (no breakdown for flap specific patients) | All: 59 % at 2 years | All: 46.1 % at 2 years | All: 80.9 % at 2 years | All: Median 21 |
| Noothanapati et al.28 | NR | NR | All: 5 / 193 (4 local + 1 free) | NR | NR | ICU stay: 14.2 (non-free flap group) v 18.3 (free flap group) |
| Meulemans et al.24 | NR | NR | All: 47.7 % (95 % l [CI] 42.0–53.2 %) at 5 years | All: 42.1 % (95 % CI 36.7–47.4 %) at 5 years | All: 5-year LRFS: 44.3 % (95 % CI 38.8–49.7 %) | NR |
| Moratin et al.27 | NR | NR | NR | NR | NR | recurrent group: 25.2 (± 19.2) |
| Chen et al.11 | NR | NR | 30 / 36 | 20 / 36 | 16 / 36 | NR |
| Piazza et al.31 | NR | NR | 100 % | NR | NR | NR |
| Kim et al.22 | swallowing, speech | All: oral swallow 68.7 %; patients who had RFF and ALT reconstruction had intelligible speech in 100 % and 59 %, respectively. | 75 % at 18 months, 54 % at 2 years. Primary 60 % 2 yr survival vs 50 % for salvage (NS) | 70 % at 1 year | Local recurrence 68 %, LN mets 21 %. Local recurrence 42 % in salvage vs 9.1 % in primary. | 31 |
| Banaszewski et al.9 | speech, swallowing, diet | All: Speech: good (7 %), moderate (50 %), poor (43 %); Swallowing: good (0 %), Moderate (56 %), Poor (44 %). | NR | NR | NR | NR |
| Chen et al.10 | Speech, swallow | All: 49 % patients achieved total oral diet at last follow up, 16 % partially G-tube dependent 36 % feeding tube dependent. Rate of total oral diet achieved was higher in patients with no prior RT 59 % v 29 % | Al: 1 year 47 %, 5 year 25 % | NR | All: Recurrence rate: 27 % local, 30 % regional, 36 % locoregional, 25 % distant | All: 13 days (7–43) |
| Han et al.18 | NR | NR | All: 1 year: 59 %, 2 years 42 %. DSS: 1 year 66 %, 2 years 56.5 % (pooled). DSS 2 years for salvaged oral cancer 80.7 %, hypopharynx 60 %, oropharynx 60 %; 5 years oral 44.4 %, HP 56.2 %, OP 41.2 %. | All: 1 year 56 %, 2 years 47 % (pooled). DFS 2 years for salvaged oral cancer 76.9 %, hypopharynx 60 %, oropharynx 40 %; 5 years oral 41.7 %, HP 30.3 %, OP 27.6 %. | NR | NR |
| Hamoir et al.17 | NR | NR | Salvage surgery group: 30 % at 2 years, 15 % at 5 years; Primary surgery group 63 % at 2 years, 32 % at 5 years | DSS: Salvage surgery group: 33 % at 2 years, 22 % at 5 years; Primary surgery group: 76 % at 2 years, 60 % at 5 years | Salvage surgery group: 37 % at 2 years, 28 % at 5 years; Primary surgery group: 81 % at 2 years, 81 at 5 years | NR |
| Anicin et al.8 | NR | NR | All: 28 % alive at the end of follow up. 72 % deaths: 60 % disease progression | NR | NR | NR |
| Llorente et al.23 | NR | NR | Salvage surgery group (n = 11): 3 years 61.8 %; 5 years 49.1 % cf non-surgical treatment group (n = 24): 3 years 24.4 %, 5 years 16.3 % | NR | 8 of 11 had recurrence: 3 local, 3 neck disease, 5 distant mets (no interval given) | NR |
| Kano et al.21 | NR | NR | Salvage surgery group: 5 year adjusted survival 34.2 % | NR | NR | Salvage surgery group: Median 18.5 |
| Esteller et al.14 | NR | NR | All: 84/105 deaths at end of follow up. | All: 52 % at 1 year, 31 % at 3 years, 21 % at 5 years | All: local control rate 46.5 %; regional control rate 37 % | All: 40 |
| Righini et al.32 | QoL after 12 months: EORTC questionnaire QLQ-C30 and QLQ-H&N35 | All: global QoL, role and emotional functioning decreased at 3/12 post salvage surgery but recovers to baseline at 12 months; physical functioning did not reach baseline at 12 months. QLQ-H&N35: significant reduction in pain at 3 months and 1 year. Swallowing and speech items at baseline at 12 months | 100 % during hospital stay | 1 year 68.4 %, 2 years 59.3 % | Progression free 38.5 % (1 year), 23.1 % 2 years | 19.5 |
For studies where figures are recorded as ‘All,’ the data is presented for entire study cohort as it was not possible to extract data for the relevant subgroup of recurrent HNSCC post radiotherapy. Where it was possible to extract data for the relevant subgroups, this is indicated in the text. Where a number is presented without indication otherwise, it represents the number for radiorecurrent HNSCC only.
NR, not recorded; CI, confidence interval; QoL, quality of life; EORTC, European Organisation for Research and Treatment of Cancer; QLQ-C30, This quality of life questionnaire is designed to measure cancer patients' physical, psychological and social functions; QLQ-H&N35, a specific quality of life questionnaire for head and neck cancer patients; MDADI, MD Anderson Dysphagia Inventory; OS, overall survival; DSS, disease-specific survival; DFS, disease-free survival; LRFS, locoregional relapse-free survival; HP, hypopharyngeal; OP, oropharyngeal; ICU, intensive care unit.
Table 3.
Summary of findings–flap outcomes.
| Salvage Treatment |
Adverse events |
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Adjunct treatment | Pedicled flaps (n = 524) | Pedicled donor site | Free flaps (n = 3998) | Free flap donor site | Flap success rate | Re-exploration for flap salvage | Total flap loss | Partial flap loss | Further operation | Fistulation | Wound breakdown | Wound infection | Thrombo-embolic event | Perioperative death | Others |
| Horn et al.20 | No | 0 | NA | All: 29 | ALT (13), RFF (5), Scap (1), 1 double flap | NR | 5/28 | 2/28 (7 %) | NR | 6/28 | NR | NR | NR | NR | 0 | 1 secondary bleeding - revision needed. 2 cardiopulmonary complications -> prolonged ITU stay |
| Mohamed et al.25 | All: RT 100 %, CT 80 % | 0 | 0 | All: 31 | NA | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NA |
| Hafström et al.16 | All: RT 35 % | 0 | 0 | All: 83 | All: RFF(58), RFF-OC (4), FFF-OC 17, ALT (4), Grac (1), RA (1) | All: 93 % | All: 8 % | All: 7 % | NR | All: return to theatre 16 % for bleeding (7 %) or compromised flaps (8 %); flap loss: 3 further free flaps + 3 regional flaps | All: 22 % | NR | All: 23 % | NR | NR | NA |
| Hirano et al.19 | 0 | 0 | 0 | 11 | FJ | 90.9 % | 1 of 11 | 1 of 11 | NR | 1 flap loss required revision with Pec Maj | 0 | NR | NR | NR | 0 | 0 radiological leak; oral intake resumed in all patients at median 14 d post-op; all patients tolerated oral food without tube feeding |
| Hirano et al.19 (comparative group) | NR | 0 | 0 | 41 (note includes the 11 from above) | FJ (29), RFFF (5), RA (4), ALT (3) | NR | NR | 2 | 1 | NR | 2 | NR | 2 | NR | NR | NR |
| Sharma et al.34 | All: CT 1.9 %, CRT 112 %, RT 17.6 % | 0 | NA | All: 58 | All: ALT (20), FFF (12), RFF (17), Other (9) | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | All: 24 % readmitted within 30 days of salvage surgery |
| D’Andrea et al.13 | All: RT 6 (11.3 %), CRT 2 (3.8 %), Immunotherapy 5 (9.4 %) | All: 12 | No details | All: 36 | No details | NR | NR | NR | NR | NR | 0 | NR | NR | NR | 3.8 % | A postoperative haemorrhage of the local site occurred 3.8 %, neck hematoma 7.6 %, post-op tracheostomy for acute respiratory distress 3.8 % |
| Noothanapati et al.28 | NR | 75 regional | Pec maj 68, Temporalis 3, Deltopectoral 3, Gastric pull-up 1; | 100 | NR | NR | Reexploration: 6.4 % of 93 in non-free flap group, 21 % in free flap group | Total flap loss: 3 non-free flap group v 7 free flap group | Partial flap loss: 7 non-free flap group v 13 free flap group | 7 free flap failures required 4 s free flaps and 3 Pec Maj flaps. 2 Pec Maj flap losses required further reconstruction with pedicled flap and prosthesis. | 22.5 % in non-free flap group; 19 % in free flap group | 37.6 % in non-free flap group;41 % in free flap group | 25.8 % in non-free flap group; 27 % in free flap group | NR | 4.3 % in non-free flap group; 1 % in free flap group | Systemic complication' 9.7 % in non-free flap group; 57 % in free flap group |
| Pazdrowsk et al.30 | NR | All: 38 | Pec Maj | All: 62 | FFF (2), RFFF (24), ALT (36) | Pedicled: 90 %, Free: 71 % | NR | PM: 10 %, FTT 29 % | NR | NR | NR | NR | NR | NR | NR | NA |
| Meulemans et al.24 | Adjuvant RT (reirradation) 14, Adjuvant CRT (including reirradiation) 2 | All: 228 | All: Pec Maj | All: 3 | RFF | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NA |
| Shankhdhar et al.33 | NR | 0 | 0 | All: 271 | All: ALT flap (52.8 %), FFF-OC (27.5 %), RFF (12.4 %), JF (3.2 %), TFL (1.6 %), AMT (1.1 %), DIEP (0.54 %), LD (0.54 %), Scap (0.27 %) | All: 90.8 % | All: Reexploration: 62 (16.2 %) cases. Venous congestion in 37.1 %, arterial insufficiency in 24.2 % | All: 9.2 % | All: 9.7 % | NR | All: 3.2 % | NR | NR | NR | NR | All: haematoma 25.8 % |
| Chen et al.11 | NR | 0 | NA | 625 | Recurrent group: ALT (517), AMT (32), Fibula (39), MSAP (4), Forearm (14), Freestyle (19) | Recurrent group: 94.9 % | NR | Recurrent group: 5.1 % | Recurrent group: 14.7 % | NR | Recurrent group: 8.6 % | NR | Recurrent group: 21.3 % | NR | NR | Recurrent group: Haematoma 5.9 % |
| Moratin et al.27 | NR | 0 | 0 | All: 220 | All: RFF (40), ALT (90), DCIA (36), FFF (34), Scap (13), Composite flap (7) | All 89.1 %, Recurrent group: 86.1 % | Recurrent group 25.3 %; All: 20 % | All 12.7 %; Recurrent group 14 %; RT group 11 % | NR | 37 required further free flap and 7 Pec Maj flap | All: 2.7 % | All: 5.9 % | NR | NR | All: 1.8 % | Bleeding: Recurrent group 3 of 79; All: Haematoma 1.4 %, bleeding requiring surgical intervention 3.2 % |
| Moltedo et al.26 | NR | 0 | 0 | All: 1604 | All: ALT (1547, 96 %), AMT (57, 4 %) | All: 96.1 % | NR | All: 4 % | All: 12.1 % | NR | All: 146 | NR | All: 346 | NR | NR | NR |
| Okamoto et al.29 | NR | 22 | Pec Maj | 0 | 0 | 100.0 % | 0 | 0 | 1 | NR | 2 of 22 | 0 | 2 of 22 | NR | NR | 1 of 22 lymphorrhoea; 0 systemic complications; 2 of 22 required hospitalization for 8 weeks |
| Chen et al.12 | CT (6), RT (4), CRT (3), none (23) | 36 | Vertical Trapezius Island Myocutaneous Flap | 0 | 0 | 91.7 % | NR | 3 | NR | NR | 2 orocutaneous fistula | NR | 2 wound dehiscence | NR | 0 | Surgical complications: 8 of 36, Medical complications 5 of 36 |
| Piazza et al.31 | NR | 0 | 0 | 55 | NR | 98.2 % | 3 (2 RF / 1 ALT) | 1 FFFR (salvage with Pec major) | 2 - salvaged | No details | 3 out of 55 | NR | NR | NR | 0 | Surgical complications: 5, medical complications 8 |
| Kim et al.22 | No | 1 | Pec Maj | 124 | RF, ALT, FFF, LD, RA, JF, ALT | NR | All: 10 cases: venous congestion 5, arterial 2, carotid blowout 3; 6 revisions: 4 successful | All: 6/124 (4.8 %) | NR | All: post-op infection in 51 cases (41.1 %): 30 cases requiring further operation | NR | NR | NR | NR | 0 | NR |
| Banaszewski et al.9 | No | 0 | NA | All: 100 | All: RFFF (66), ALT (32), FFF (2) | All: 95 % | All: 6 % revision of anastomoses within 48 h (2 in primary, 4 in salvage) | All: 5/100 (5 %) | unclear | NR | 15 % salivary fistula (required surgical intervention) | 28 % post op complication healed by secondary intention | 33 % (26–48 %), despite peri‑op abx | NR | 0 | Local tumour recurrence mentioned as post-op complication for 4 patients requiring subsequent operation |
| Chen et al.10 | All: 74 % had RT; 49 % had chemoRT | 0 | NA | All: 200 | All: ALT/Scap/LD/AMT (132), radial/ulnar forearm (44), FFF (24) | NR | NR | 8/200 (4 %) | NR | NR | NR | NR | NR | NR | 0 | NR |
| Han et al.18 | All: RT (23 %), Re-RT (11 %), CT (3 %), CRT (56 %) | 0 | NA | All: 48 | All: RA (19), fibula (12), ALT (11), RFF (4), subscap (2) | 100.0 % | NR | 0/48 (0 %) | All: 4/48 | NR | NR | NR | All: 2/48 | NR | 0 | All: Pulmonary complication 3/48; Speech (good 7 %, moderate 50 %, poor 43 %). Swallow (good 0 %, mod 56 %, poor 44 %) |
| Hamoir et al.17 | No | NR | NA | NR | NR | NR | NR | All: 9/57 (15.8 %) either total or partial flap loss | NR | NR | All: pharyngocutaneous fistula 16/97 (16.5 %) | NR | NR | NR | 1 | All: Postop haemorrhage in 5 patients, required intervention. Haemodynamic complication in 4/39 |
| Anicin et al.8 | 0 | 15 | Pec Maj | 0 | NA | All: 92.5 % | NR | NR | 3/20 (including 1 patient who had recurrence following surgery only for primary cancer) | NR | NR | NR | NR | NR | NR | NR |
| Gordin et al.15 | NR | 0 | NA | Recurrence group: 26 | RFFF (15), FFF (3), ALT (1), RA (7) | 100.0 % | NR | 0 | Recurrence group: 1/26 | 1 patient had hardware exposure requiring further RFFF | 11 cases of laryngectomy/laryngophaaryngectomy defects repaired wtih RFFF; 4 pharyngocutaneous fistulae; 3 repaired with pectoralis major flaps (4 resumed adequate oral intake to allow removal of gastrostomy tubes) | 1/24 | NR | NR | NR | NR |
| Llorente et al.23 | All: RT (29 %), CT (11 %), CRT (6 %) | 0 | NA | All: 259 | All: ALT (90), RFF (108), Parascap (28), Scap-parascap (10), FJ (19), FFF (2), RA (2) | 92.0 % | NR | All: 20/259 (7.7 %) | All: 6/259 (2.3 %) | 5 cases required 2nd free flap, 2 cases required local flap, 4 pec major myocutaneous flap | NR | NR | All 3 (1 %) | NR | All: 7 (3 %) | All: Haemorrhage 21 (8 %) |
| Kano et al.21 | RT (1), CT (4) | 0 | 0 | 10 | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | 0 | 5 patients depended on a feeding tube after salvage surgery |
| Esteller et al.14 | Salvage surgery group: RT (n = 3), CT (n = 3) | 7 | Pec Maj | 13 | RA (10), ALT (1), FFF (2) | 92.3 % | 1 | Pedicled: 0 of 7; Free: 1 of 13 | NR | 4 of 6 with pharyngocutaneous fistula treated with Pec Maj flap; 1 free flap failure required further reconstruction with Pec Maj flap | All: 6/32 (with bleeding requiring urgent wound revision in 3) | NR | NR | NR | NR | All: 2/32 post-op bleeding requiring wound revision; 9/32 had complications related to excision of primary tumour. |
| Righini et al.32 | All: 8/105 (7.5 %) adjuvant CRT | 90 | Pec Maj or LD (n = 80); temporofrontal flap (n = 10) | 0 | NA | NR | NR | NR | 23 % | All: 30/105 surgical revision (12 fistula, 18 partial necrosis and/or partial wound dehiscence) | All: Orocutaneous fistula 11.5 % | All: 23 % with partial flap necrosis and/or partial wound dehiscence | All: Pneumonia 10 (9.6 %); decompensation of diabetes 5 (4.8 %), GI bleed 1 (0.9 %) | All: PE 3 (2.8 %) | All: 6 % | All: Stroke 0.9 %, Pneumonia 9.6 %; decompensation of diabetes 4.8 %, GI bleed 10.9 %; incomplete tumour resection in 40 %. |
For studies where figures are recorded as ‘All,’ the data is presented for entire study cohort as it was not possible to extract data for the relevant subgroup of recurrent HNSCC post radiotherapy.
ALT, anterolateral thigh; AMT, anteromedial thigh; DCIA, deep circumflex iliac artery; DIEP, deep inferior epigastric perforator; FFF, free fibular flap; FJ, free jejunum; LD, latissimus dorsi; MSAP, medial sural artery perforator; OC, osteocutaneous; Parascap, parascaplar; Pec Maj, pectoralis major; RA, rectus abdomins; RFF, radial forearm flap; Scap, scapular; Subscap, subscapular; TFL, tensor fascia lata; NR, not recorded.
The data design did not allow for analysis of patient reported outcomes or oncological outcomes (survival and locoregional control).
The most commonly reported free flaps were ALT, RFF and fibular flaps. Only four studies reported the use of mucosal free flaps.19,22,23,33 The most common pedicled flap was the Pectoralis Major myocutaneous flap. The most common subsites involved were the oral cavity and oropharynx, and larynx. Total and partial loss of flap ranged from 0 to 29 % and 0–14.7 %, respectively for free flaps. Most studies reported a total loss rate of <10 %. For pedicled flaps, total and partial loss of flap ranged from 0 to 10 % and 0 to 9.3 %, respectively. However, these are estimations as the reported rates often included patients who did not have radiorecurrent HNSCC and it was not possible to extract more granular data.
Discussion
We found no evidence of any differences between the two groups in survival rates, patient-reported outcomes (PRO), and adverse events including flap survival, but we judge the certainty of this evidence to be very low. Microsurgery in a previously irradiated field is perceived to be a risk factor for free flap reconstruction. Whilst the studies did not allow an in depth analysis of pedicled versus free flap reconstruction in recurrent HNSCC after radiotherapy, they did suggest that high success rates can be achieved and that quality of life can be preserved.10,18,20,22,23 In a large propensity score matching study, Chen et al.11 reported a higher failure rate for free flap reconstruction for recurrent head and neck cancer compared to primary disease (5.1 % v 3.1 %) but there was no significant difference among the matched study population. They also found no significance difference for flap loss and secondary outcomes and hence attributed the different failure rates to different baseline characteristics. Gordin and Ducic15 showed that free flap reconstruction could be reliably successful even in patients who have had multiple courses of radiotherapy, reporting a 100 % flap success rate in 26 flaps on 24 patients. Moratin et al.27 demonstrated their experience of free flap reconstruction giving a reliably good outcome even in the context of recurrent head and neck cancer with a total flap loss rate of 11 % after radiotherapy. Shankhdar et al.33 reported a high reexploration rate of 16.2 % despite the overall acceptable flap survival rate. Llorente et al.23 found that 14 of the 20 patients who had total loss of the free flap reconstruction was in a previously irradiated field although they were not able to identify any predictive factor.
Noothanpati et al.28 found similar total flap loss rates, 3 % in non-free flaps versus 7 % in free flaps; as well as partial flap loss rates 7 % non-free flaps versus 13 in free flap groups. Their uni- and multivariate analysis did not identify any significant predictor of flap related complication. They found patients were more likely to have a non-free flap reconstruction with previous radiotherapy and commented that there was a selection bias in allocating patients to the different flap options. Pazdrowski et al.30 also reported their experience of salvage reconstruction for recurrent head and neck cancer and found total flap loss rates of 10 % in pectoralis major flaps and 71 % in free flaps; and partial flap loss rates of 10 % in pectoralis major flaps and 29 % in free flaps. These groups however included patients who did not have radiotherapy for their primary disease, ie. not radiorecurrent HNSCC. There was insufficient data to compare these outcomes. However, they did show that surgical time for pectoralis major flap reconstruction is significantly shorter compared to free flap (4.3 h v 7.1 h). This is an important consideration given the comorbidities of this cohort of patients and also the resources available in different healthcare settings.
Other studies have also demonstrated that pedicled flaps are not immune to total or partial flap loss in the irradiated field. Righini et al.32 reported their experience of 90 pedicled flaps (pectoralis major, latissimus dorsi and temporofrontal flaps) with 23 % partial flap loss. Ancini et al.8 presented their experience of 15 pectoralis major flaps for primary and recurrent HNSCC and 3 of 20 had partial flap loss. This cohort included primary cancers where there was no previous irradiation. For recurrent nasopharyngeal carcinoma following RT, Chen et al12 found that the conditions were not appropriate for microvascular free flaps and reported their experience with a vertical trapezius island myocutaneous flap with a total loss rate of 8.3 %.
Esteller et al.14 investigated the outcomes of salvage surgery following recurrence of HNSCC treated with CRT. They found that salvage surgery performed within 6 months of CRT led to an increased rate of complications (20 v 12 %).
It is important to note that whilst flap survival is an important clinician-reported outcome, the most important outcomes should be relevant to the patient experience including their quality of life and function. The reporting of included studies have not allowed comparative analysis of these outcomes.
Radiation therapy has been found to be a significant risk factor for flap failure and complications.5 The available data suggest that both pedicled and free flaps offer reliable reconstructive solutions for this cohort of patients. Each flap type has its own advantages and disadvantages, but the technique should be chosen on a case by case basis, taking patient fitness, defect characteristics, prognosis, surgical expertise and resources available into account.
Overall completeness and applicability of evidence
The studies included in this review involved participants with recurrent head and neck cancer after radiotherapy requiring salvage reconstruction using either pedicled or free flap techniques. However, the completeness and applicability of the evidence were limited. Notable challenges were in identifying the relevant study participants and variable reporting of relevant outcomes. Studies focussed on reconstructive technique tended to include patients who had multiple indications for salvage surgery other than recurrent HNSCC e.g. secondary primary cancers, persistent HNSCC and non-HNSCC; they were also less rigorous in reporting oncological outcomes such as survival. By contrast, studies focused on oncological aspects of management tended to include patients with recurrent disease with and without flap reconstruction and were less rigorous in reporting reconstructive outcome-related data such as flap survival, cause of failure and flap-related complications. Most studies did not provide subgroup datasets for the granularity necessary for a meta-analysis of flap outcomes for recurrent HNSCC.
Furthermore, study reports often did not provide comprehensive details about the full management protocols employed by the units. For instance, primary cancer treatment regimens or TNM stage at presentation were not always explicitly stated. Additionally, it was frequently unclear whether Intensity-Modulated Radiation Therapy or traditional Radiation Therapy was used, although we attempted to exclude studies focusing on traditional RT outcomes by selecting studies conducted after 1990, as these outcomes are no longer relevant to modern H&N treatment.
The lack of evidence must be viewed in the context of the significant heterogeneity in head and neck cancer care across different countries and healthcare systems. This heterogeneity is particularly relevant for complex H&N cancer, where outcomes are time-sensitive and highly dependent on resource availability.
Overall, the included studies reported few outcomes and notably lacked patient-relevant outcomes including quality of life. While the absence of these outcomes is not unexpected, it limits our ability to present a comprehensive picture of the benefits and harms of the treatment options.
The certainty of the evidence for all outcomes in this review was very low due to limitations in study design and outcome reporting. Furthermore, the number of studies was insufficient to effectively evaluate inconsistency or publication bias.
Although non-randomised observational studies exist on flap salvage reconstruction for recurrent HNSCC, this review identifies an important evidence gap in the salvage treatment of people with recurrent HNSCC following radiotherapy where flap reconstruction is considered a high-risk procedure. It does not provide conclusive evidence to support or oppose the use of pedicled versus free flaps in the context of previous radiotherapy for HNSCC. Comparative or propensity score matching studies with adequate power with appropriate oncologic and flap-related outcome reporting are necessary to determine whether pedicled or free flap reconstruction leads to better outcomes in the salvage reconstruction of recurrent HNSCC following radiotherapy.
Conflict of interest
The authors have no conflict of interest to disclose.
Acknowledgments
Acknowledgements
This study did not receive any financial support.
Funding
None.
Ethical approval
Not required.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jpra.2025.05.015.
Appendix. Supplementary materials
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