Conservative treatment for advanced T3–T4 laryngeal cancer: meta-analysis of key oncological outcomes

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Conclusion The two surgical techniques are both valid conservative surgical options for advanced laryngeal cancer treatment.

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  Vol.:(0123456789)  1 3 Eur Arch Otorhinolaryngol DOI 10.1007/s00405-017-4799-x REVIEW ARTICLE Conservative treatment for advanced T3–T4 laryngeal cancer: meta-analysis of key oncological outcomes Giuditta Mannelli 1  · Maria Silvia Lazio 1  · Paolo Luparello 1  · Oreste Gallo 1   Received: 7 September 2017 / Accepted: 2 November 2017 © Springer-Verlag GmbH Germany, part of Springer Nature 2017 Conclusion  The two surgical techniques are both valid conservative surgical options for advanced laryngeal can-cer treatment. Keywords  Systematic review · Meta-analysis · Advanced laryngeal carcinoma · Surgical conservative treatment · Oncological outcomes. Introduction Laryngeal cancer is one of the most common cancer of the upper aerodigestive tract and the second among head and neck cancers after skin malignancies. Most of laryngeal neoplasms show squamous cell carcinoma (SCC) histol-ogy, accounting for 85–95% of laryngeal malignant tumours whose incidence is approximately 11,000–13,000 of cases annually in the USA [1].Advanced T stage (T3–T4) laryngeal cancer, encompass a heterogeneous variety of different lesions, each character-ised by distinct clinical presentation, biological behaviours and prognosis. Thus, neoplastic pathways of tumour spread, should be carefully considered during therapeutic planning [2–4]. Currently, different modalities of treatment are avail-able for all subtypes of T3 and T4 laryngeal tumours and, although oncologic outcome does remain the first goal, preservation of laryngeal functions and quality of life has progressively gained an important role heavily influencing the decision-making process of surgeons [5]. Since 1871, when Van Luschka introduced an accurate anatomical description of laryngeal framework by set-ting the body for future laryngeal surgery [6], over the last decades, the evolution of the treatment of laryngeal cancer has passed through different attitudes and aims, Abstract   Goal  Controversies exist regarding the treatment of advanced laryngeal carcinomas. The purpose of this system-atic review was to evaluate the oncologic outcomes of both transoral laser and open partial laryngectomies for advanced (T3–T4) squamous cell laryngeal cancers management.  Introduction  A systematic review of literature was led searching for articles mentioning the following terms: advanced (T3–T4) laryngeal cancer AND laser; AND open partial laryngectomy; AND transoral laser microsurgery; AND cordectomy; AND conservative surgery; AND tra-cheohyoidopexy or tracheohyoidoepiglottopexy; AND supratracheal partial laryngectomy; AND supracricoid par-tial laryngectomy; AND cricohyoidopexy or cricohyoidoe-piglottopexy. Then a quantitative analysis was carried on papers published after 1980.  Discussion  The search identified 110 publications, and a total of 21 articles satisfied inclusion criteria and were selected for quantitative synthesis. 10 out of 21 studies had a good quality score, 10 were fair and only one rated a poor score. The pooled disease-free survival (DFS) was 79% (95% CI 74–85), and pooled overall survival (OS) was 71% (95% CI 64–78) at 5 years from all 1921 patients included in the study, with significant heterogeneity (  I  2  = 89.7% and  I  2  = 90.4%), respectively. Significant heterogeneity value (  p  = 0.118) was seen by comparing transoral laser and open partial laryngectomies in terms of DFS.   *  Giuditta Mannelli mannelli.giuditta@gmail.com 1  Clinic of Otorhinolaryngology, Head and Neck Surgery, Department of Translational Surgery and Medicine, University of Florence, Largo Brambilla 3, 50134 Firenze, Italy   Eur Arch Otorhinolaryngol  1 3 and in this scenario total laryngectomy (TL) has been the mainstay of treatment for decades. Afterwards, voice pres-ervation has gained a crucial role in treatment planning and patients’ expectations, consequently, patients have progressively begun to undergo surgical and nonsurgical preserving therapies [7]. The increasing accuracy of diag-nostic techniques have gradually ensured a better patient selection, thus allowing the introduction of conservative surgery procedures in clinical practice. In fact, the propor-tion of patients receiving TL has declined from 74% in 1999 to 26% in 2007 [8] and open partial laryngectomy (OPL) together with transoral laser microsurgery (TLM), have been progressively introduced for the treatment of intermediate and advanced laryngeal tumours. Since the 1970s’ when Labayle and Piquet introduced supracricoid partial laryngectomy for glottic cancer treatment [9, 10] and Steiner commenced TLM for laryngeal carcinomas in 1979 [11], laryngeal preservation procedures have paved the pathway for the contemporary management of laryn-geal cancer. However, whereas chemoradiation therapy protocols have a tough scientific basis [12–14], indica- tions for conservative surgery still wait for full validation.Many publications, indeed, confirming the oncologi-cal and functional benefits of both OPL and TLM exist, and they show that both surgical procedures offer similar local control rates and overall survival to total laryngec-tomy for advanced laryngeal cancer treatment [15, 16], by ensuring fair post treatment organ functions when appro-priate patients selection has been performed. In addition, consequently to the increasing use of chemotherapy with concurrent radiotherapy organ preservation strategies to treat advanced laryngeal cancer, OPLs have established an important and oncologically reliable role in the man-agement of recurrent radio-resistant laryngeal carcinoma [17, 18]. In this respect, treatment plan selection might respect patients’ needs, by aiming and demanding not only onco-logical but also functional results, in accordance with sur-geons’ skills and knowledge.Given this background, we performed a systematic review of English language literature in an attempt to more robustly establish the local control and overall survival in conservation laryngeal surgery for advanced T stage cancers. The objective of this review and meta-analysis was to synthesise the oncological outcomes following laryngeal surgical preservation protocol, including both open partial and transoral laser procedures, performed as primary therapeutic options for advanced T3 and T4 laryn-geal squamous cell carcinoma through the analysis of the latest reports in laryngeal cancer management published in the past 35 years, to give a full view about the most reli-able therapeutic options for this type of patients. Materials and methods The systematic review was performed using independently developed search strategies in literature review methodol-ogy, and it was written in accordance with PRISMA State-ment (http://www.prisma-statement.org) [19], to guarantee a scientific strategy of research to limit bias by a systematic assembly, critical appraisal and synthesis of all the most relevant studies published on this topic [20, 21]. The databases interrogated included PubMed Clinical Queries http://www.ncbi.nlm.nih.gov. Reference lists from identified articles were searched and cross-referenced to identify additional relevant articles, and national experts in the field were contacted to identify unpublished data.The search terms included the following various combi-nations to maximise the yield: advanced (T3–T4) laryngeal cancer AND laser; AND open partial laryngectomy (OPL); AND transoral laser microsurgery (TLM); AND cordec-tomy; AND conservative surgery; AND tracheohyoido-pexy (THIP) or tracheohyoidoepiglotto-pexy (THIEP); AND supratracheal partial laryngectomy (STPL); AND supracri-coid partial laryngectomy (SCPL) ; AND cricohyoidopexy (CHP) or cricohyoidoepiglotto-pexy (CHEP).The search was performed for the first time on January 2016 and was set to automatically update periodically until December 2016.First, duplicates were removed electronically. Then abstracts were reviewed to exclude obviously irrelevant articles. Non-English language papers and duplicates were excluded. Experimental studies and papers dealing with pathologies other than advanced lesions of the larynx were excluded.The inclusion criteria were set a priori  and deliberately kept wide to encompass as many articles as possible without compromising the validity of the results, and they included articles: (1) published from 1980 onwards, (2) reporting published series of > 10 patients underwent partial laryn-geal procedures with a minimum of 5 years follow up, (3) about conservation laryngeal procedures excluding total lar-yngectomy, (4) reporting data distinguishes results of partial laryngeal procedures divided into: TLM, CHP, CHEP, THIP, THIEP, SCL, HPL, Cordectomy, (5) with a clear description of TNM tumour stage and treatment selection criteria for primary laryngeal SCC, and (6) clear description of local control rate at 60 months.The search excluded articles published before 1980 because the surgical repertoire until the 1960s was pri-marily restricted to TL as therapeutic surgical option for advanced laryngeal cancer and because reporting outcomes on relatively small case series with highly variable local control rates and functional outcomes. Furthermore, SCPL, although described much earlier, became more popular and common in clinical practice since the 1970s. Consequently,  Eur Arch Otorhinolaryngol  1 3 we considered articles published starting from the 1980s onwards to allow time for the flattening of the learning curve, together with the entrance in the surgical practice of more technological procedures, such as TLM for supraglot-tic lesions, which obviously belong to the latest years of our analysis.We filtered the studies to ensure that only data from cen-tres that had published on at least 10 patients were included in the review; this was done as a quality assurance measure as there are several case series in the literature, which have published the results of small numbers of cases spanning several years. Non-English language papers and duplicates were excluded.All data were independently extracted by two authors and quality assessed. Eligibility for inclusion was sepa-rately assessed and when in doubt discussed and decided by consensus.We chose overall survival (OS) and local control rate (LC) at 60 months as the primary measure of oncological outcome. Possible bias including age, existing co-morbidity, access and availability to treatment for other medical condi-tions and incidence of second primary tumours. Similarly disease-free survival (DFS) will depend on the incidence of regional and distant metastasis.Abstracts were analysed to identify papers that fulfilled inclusion criteria and a first qualitative and descriptive review-analysis of selected articles was carried on; whilst, exclusively, publications clearly describing their aim and objectives, their inclusion and exclusion criteria, with clear or detachable statistical data, reporting adequate survival interval at 60 months from conservative surgical primary treatment, and well describing the surgical techniques and post-operative complications, were included in our meta-analysis. For articles not reporting raw data, letters were sent to the corresponding authors requesting them, otherwise they were excluded from the quantitative analysis. Raw data from the meta-analysis were entered into the appropriate contingency tables to allow calculation of OS and DFS, Younden’s index, for each surgical technique: TLM, CHP, CHEP, THIP, THIEP, SCL, HPL, Cordectomy.Given the variable reporting practice, the use of outcome measures that cannot be directly compared and the need for different search strategy, we did not include functional out-come in this meta-analysis as a criterion for inclusion. Study characteristics and quality assessment All included papers were graded using the NICE scoring scale for retrospective case series (Available at: http://www.nice.org.uk/nicemedia/pdf/Appendix_04_qualityofcase_series_form_preop.pdf ). This is a scoring scale with eight items, with each item scoring zero or one based on the study methods (Yes = 1; No = 0). Scores of ≥ 6 are considered to indicate a good quality study, scores between four and five as fair and those studies with a score of three are treated as poor quality (Table 1). Statistical analysis Fisher’s exact test was used for statistical analysis of categor-ical data for the descriptive review, and a value of  p  < 0.05 was considered significant.The pooled estimate of each statistic was calculated after Freeman–Tukey double arcsine transformation to stabilise the variances. A random effect model was specified, using the method of DerSimonian and Laird, with the estimate of heterogeneity being taken from the inverse-variance fixed-effect model. Heterogeneity is also quantified using the I-squared measure.Heterogeneity (or absence of homogeneity) of the results between the studies is assessed graphically by forest plots and statistically using the quantity  I  2  that describes the per-centage of total variation across studies that is attributable to heterogeneity rather than chance [22, 23]. This is a measure of heterogeneity between the studies and ranges from 0 to 100%; high figures indicate greater heterogeneity in the data.When studies have low heterogeneity (pragmatically,  I  2  < 25%), the differences between reported outcomes can be explained simply by the observed natural differences between patients. In this case, we can consider that all Table 1 Quality assessment for case seriesQuality assessment for case series1Case series collected in more than 1 center (i.e. a multicentric study)2Is the hypothesis/aim/objective of the study clearly described?3Are the inclusion and exclusion criteria (case definition) celarly reported?4Is there a clear definition of the outcomes reported?5Were data collected prospectively?6Is there an explicit statement that patients were recruited consecutively?7Are the main findings of the study clearly described?8Are outcomes stratified (i.e. by disease stage, abnormal test results, patient characteristics)?   Eur Arch Otorhinolaryngol  1 3 patients are part of the same larger pool. A fixed-effects meta-analysis is appropriate in which each  patient   is given approximately equal weight. However, with high heteroge-neity, the studies differ by more than can be explained by intra-patients effects. This implies that there were differ-ences in the patients studies, in the treatment interventions, or in the outcome measures. In this case, a random-effects meta-analysis is appropriate in which each study  is given more equal weight.All analyses were performed using STATA version 13 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). Results The search strategy identified 110 articles in Medline from 1980 to the search date. They were selected, imported into Endnote, and the duplicates were removed. The removal of duplicates, non-English language works and of articles about other items rather than primary conservative surgical treatment for advanced laryngeal cancer yielded a total of 71 publications. 25 studies out of 71 were excluded from our analysis because reporting report, including letters or reviews, or not including advanced T stage laryngeal cancer but focusing only and general tumour stage. Therefore, 46 articles were considered for the qualitative systematic review whilst, only 21 out of 46, reporting on the outcomes of 1918 patients, were included in the meta-analysis.The various stages of systematically assessing the abstracts and reasons for exclusion from the review are described in Fig. 1.As for their quality, as assessed by the quality assessment criteria outlined above, 10 papers scored six or seven, 10 papers scored four or five and one paper scored three.Of the included patients, 1448 and 470 patients were reported to have T3 and T4 tumour respectively, accordingly to the pathological AJCC classification [2].The surgical procedures described in the 21 papers, included: transoral laser microsurgery (TLM), cricohyoidoe-piglotto-pexy (CHEP), cricohyoidopexy (CHP), tracheohy-oidoepiglotto-pexy (THIEP), tracheoepiglotto-pexy (THIP); supra tracheal partial laryngectomy (STLP), supracricoid partial laryngectomy (SCPL), horizontal partial laryngec-tomy (HPL), as reported in Table 2.Adjuvant radiotherapy (RT) was not systematically administered by authors to every patient to avoid its poten-tial collateral effects on their functional outcomes [31, 39]. The presence of positive resection margins after open par-tial surgery or patients with persistent tumour after transoral margins re-resection, large extra-laryngeal tumour extent, pathological report with presence of perineurial invasion and angioembolization, multiple positive lymph nodes and/or neck nodes with extra capsular spread (ECS) of the disease, represented the main conditions for adjuvant RT treatment indication.Only three out of the 21 articles did not well specify indi-cations and sites of adjuvant treatment [7, 34, 37]; on the other hand, the remaining 18 papers reported reasons and sites of post-operative RT. Table 2 summarises the num-ber of patients who underwent adjuvant RT, where primary tumour and neck sites are reported separately.Accordingly to our inclusion criteria, the follow-up dura-tion time ranged from 12 to 120 months, with a median fol-low-up of 60 months.The pooled OS (overall survival) was 71% (95% CI 64–78). Heterogeneity tests revealed significant heteroge-neity (  I  2  = 90.4%) which is to be expected given the wide spectrum of operations, outcomes and follow-up times reported. The lowest OS rate was 49.80% [32], with two studies reporting 94 and 93.80% OS rates [34, 42]. The for- est plot is shown in Fig. 2.The pooled DFS (disease-free survival) was 79% (95% CI 74–85) with significant heterogeneity (  I  2  = 89.7%). The low-est DFS rate was 52.54% [32], with other two studies both reporting 93.75% of DFS [33, 42] and one study showing no recurrence event [35]. The forest plot is shown in Fig. 3. Figures 4, 5 show forest forest plot by technique for OS and DFS, respectively. Here we divided surgical procedures into two different groups: (1) CLOSED techniques—TLM; vs. (2) OPEN techniques, including CHEP, CHP, THIEP, THIP, STLP, SCPL and HPL.The pooled OS was the same in the two subgroups (het-erogeneity between groups,  p  value of 0.518) with 69% (95% CI 59–79) pooled OS rate in the closed technique group and 73% (95% CI 66–81) pooled OR rate in the open technique group. The pooled DFS was quite different in the two sub-groups (heterogeneity between groups, p value of 0.118) with 76% (95% CI 69–83) pooled DSS rate in the closed technique group and 83% (95% CI 78–89) pooled DFS rate in the open technique group. Discussion Despite its efficacy as an oncologic procedure, total lar-yngectomy (TL) implies complete loss of the larynx and represents a devastating event with significant subsequent diminution of quality of life for many individuals. Mod-ern voice restoration procedures, have greatly improved the quality of life after TL but, since the 1980s it became apparent that in selected cases removal of the entire larynx was not necessary. In fact, conservation surgery complies with oncologic surgical principles and it has been shown that long-term survival rates are comparable to TL on well selected same advanced laryngeal lesions. In this respect,  Eur Arch Otorhinolaryngol  1 3 Fig. 1 This flow chart illustrates the process that was used to select articles for the review
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