Introduction
Head and neck cancer is diagnosed worldwide in approximately 550 000 patients and is associated with 79 000 deaths annually.Reference Ferlay, Shin, Bray, Forman, Mathers and Parkin1 The development and increasing incidence of oropharyngeal squamous cell carcinoma (SCC) has been strongly associated with the human papilloma virus (HPV).Reference Chaturvedi, Engels, Pfeiffer, Hernandez, Xiao and Kim2, Reference Hong, Grulich, Jones, Lee, Garland and Dobbins3 Studies have found positive HPV status to be a prognostic factor, with generally improved survival outcomes for HPV-positive patients, who are usually younger and non-smokers.Reference Gillison and Lowy4 However, recurrences after treatment for oropharyngeal SCC occur despite advances in treatment modalities.Reference Liu, Gullane, Brown and Irish5
Studies have identified recurrences to be higher in patients with extracapsular nodal spread and inadequate resection margins.Reference Johnson, Barnes, Myers, Schramm, Borochovitz and Sigler6–Reference Vikram, Strong, Shah and Spiro8 Despite the advances in treatment modalities, the long-term survival of patients who develop recurrences has been reported as ranging from 23 to 35 per cent.Reference Warnakulasuriya9, Reference Jesse and Sugarbaker10 In patients treated with primary radiotherapy (RT), local recurrence has been found to occur more commonly than regional and distant recurrences. However, regional disease is associated with increased disease-related death.Reference Goodwin11 Thus, salvage surgery is usually considered for these patients, especially if the patient's initial treatment was with RT. However, extensive salvage surgery is associated with higher risks of morbidity and mortality.Reference Goodwin11
In light of the rising incidence of oropharyngeal SCC, this paper aims to update the Goodwin (2000) paper on survival rates following salvage surgery.Reference Goodwin11 This systematic review presents overall and disease-free survival outcomes of patients with stage I–IV recurrent oropharyngeal SCC who underwent salvage surgery with curative intent.
Materials and methods
Medline (PubMed), the Cumulative Index to Nursing and Allied Health Literature, Embase, and the Cochrane Database of Systematic Reviews were searched for English-language studies, from the inception of the databases to 17 March 2016. An initial limited search of PubMed was performed using the terms ‘oropharyngeal squamous cell carcinoma’, ‘salvage surgery’ and ‘survival’. Through this process, additional relevant keywords and index terms were identified. With further assistance from a research librarian, a detailed and comprehensive search strategy was generated for all included databases (Appendix 1). A second search utilising all identified keywords and index terms was applied across all databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) guidelines (Figure 1).
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram, illustrating the process of study inclusion and exclusion.
Studies with patients aged 18 years or older, with a histological diagnosis of oropharyngeal SCC, were included. The initial treatment of malignancy included either: primary surgery and adjuvant RT, primary surgery and adjuvant chemoradiotherapy, primary RT alone, or primary chemoradiotherapy aimed at curative intent. Only patients undergoing salvage surgery (with or without adjuvant therapy) for the treatment of residual or local and/or regional recurrences were included. Exclusion criteria included: patients with distant metastasis at diagnosis or the presence of other malignancies, including second primary malignancies; and patients treated with salvage RT or salvage chemoradiotherapy aimed at palliation.
Outcomes of interest for this review are related to survival rates following salvage surgery. Secondary outcomes included: time to recurrence following primary treatment and salvage surgery, staging at time of recurrence, post-operative complications, and factors associated with mortality and recurrence after salvage surgery.
Quality appraisal
Papers retrieved that met all inclusion criteria were assessed by two independent reviewers (SSK, EHO) for methodological quality using standardised critical appraisal instruments from the Joanna Briggs Institute (‘JBI’) Meta-Analysis of Statistics Assessment and Review Instrument (Appendix 2).Reference Kainickal, Shishak, Kumar, Rafi, George and Ramdas12 Any disagreements that arose between the reviewers were resolved through discussion. Articles with methodological scores of 5 or less were classified as high risk for bias and thus were excluded from the study.
Data extraction
Data were extracted from papers included in the review using the standardised data extraction tool from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (Appendix 3).Reference Kainickal, Shishak, Kumar, Rafi, George and Ramdas12 The data extracted included population, primary treatment modality, salvage treatment modality, subsite of malignancy, tumour–node–metastasis (TNM) classification at the time of salvage surgery, malignancy stage at the time of salvage surgery, p16 status, mortality rate, time to recurrence, post-operative complications and factors associated with mortality. If relevant data were missing or incomplete, this information was requested from the study authors. If the data could not be provided, the study was excluded.
Results
The search identified a total of 570 studies, with 379 remaining after the removal of duplicates. Titles and abstracts were reviewed against inclusion criteria, leading to the further exclusion of 286 studies. Ninety-three studies were retrieved for detailed examination of the full text, which resulted in the exclusion of 71 studies that did not meet the inclusion criteria. The 22 remaining studies reported upon the survival outcomes of 776 patients who underwent salvage surgery for recurrent or residual oropharyngeal SCC. The reference lists of all selected studies were searched for additional studies. No further studies were identified.
The included studies at this stage consisted of 21 case series and 1 case–control study. Methodological quality ranged from 4 to 9 on appraisal criteria (Appendix 4). Confounding factors included varying malignancy stages, differing subsites and recurrence locations, and diverse primary treatment modalities. Four studies scored 5 on the critical appraisal and were excluded because of a high risk of bias.Reference Chen, Yang, Zhou, Fan, Zhang and Wang13–Reference Nussbaum, Kagan and Chan16 These studies did not include detailed descriptions of included patients, statistical analysis was not described, and patients who withdrew or were lost to follow up were not described or included (Appendix 3).
The included studies were conducted from 1964 to 2013, with the patient population consisting predominantly of males (82 per cent), with a mean age of 60 years. All patients had oropharyngeal SCC ranging from stage I to stage IV (American Joint Committee on Cancer classification). The majority of patients had initial treatment with primary RT, with or without adjuvant chemotherapy.Reference Aziz, Nyman and Edstrom17–Reference Omura, Saito, Ando, Kobayashi, Ebihara and Yamasoba29 Four of the included studies utilised surgery as a form of primary treatment.Reference Agra, Carvalho, Ulbrich, de Campos, Martins and Magrin30–Reference White, Ford, Bush, Holsinger, Moore and Ghanem33 The mean time to recurrence following primary treatment was 15 months.Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20, Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Regueiro, de la Torre, Valcarcel, Magallon and Aragon27, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28, Reference Röösli, Studer and Stoeckli32
Heterogeneity in the included studies concerned differences in study designs, surgical resections, malignancy stages and subsites, and primary treatment modalities. Given the heterogeneity of the studies included in this review, a meta-analysis was not performed. Thus, a summary table (Table I) with a narrative summary and discussion was chosen to highlight the analysis.
Studies included in systematic review
NR = not reported; RT = radiotherapy; SD = standard deviation; CRT = chemoradiotherapy; TORS = transoral robotic surgery
Overall survival following salvage surgery (with or without adjuvant therapies) was discussed in 14 of the included studies (Table II). The mean overall survival rate following salvage surgery was 52 per cent in the second year, with a steady decrease to 30 per cent at five years following salvage surgery. Röösli et al. found the five-year survival rate after salvage surgery following primary RT to be 25 per cent, compared with a rate of 40 per cent for primary surgery with adjuvant RT.Reference Röösli, Studer and Stoeckli32 Bachar et al. found a rapid decrease in survival rate within the first year following salvage surgery.Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18 Patel et al. reported a statistically significant difference between patients treated with salvage surgery and patients who did not undergo salvage treatment.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 The overall survival rates in patients who did not receive salvage treatment were 19 per cent, 9 per cent and 2 per cent, at two, three and five years, respectively. Studies conducted prior to 1990 had mean two- and five-year survival rates of 30.3 per cent and 24.2 per cent,Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Basso Ricci, Grandi and Salvatori19, Reference Gehanno, Depondt, Guedon, Kebaili and Koka21, Reference Agra, Carvalho, Ulbrich, de Campos, Martins and Magrin30, Reference Shrewsbury, Adams, Duvall, Maisel and Haselow34 whereas studies conducted after 1990 had respective mean rates of 64.9 per cent and 32.6 per cent.Reference Aziz, Nyman and Edstrom17, Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20, Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28, Reference Röösli, Studer and Stoeckli32, Reference White, Ford, Bush, Holsinger, Moore and Ghanem33
Overall survival following salvage surgery with or without adjuvant therapy
OS = overall survival; NR = not reported; TORS = transoral robotic surgery
A summary of disease-specific and recurrence-free survival rates, TNM stage at the time of salvage surgery, and post-operative complications, is shown in Table III, IV and V.
Disease-specific and recurrence-free survival following salvage surgery with or without adjuvant therapy
DSS = disease-specific survival; RFS = recurrence-free survival; NR = not reported; TORS = transoral robotic surgery
Stage, site and time to recurrence
NR = not reported
Post-operative complications
TORS = transoral robotic surgery
The identified factors associated with decreased survival were: advanced overall disease stage (III and IV),Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20 advanced tumour (T) stage (T3+),Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20, Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 advanced nodal (N) stage (N2–3),Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22, Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 histological grading,Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22 tongue base involvement,Reference Gehanno, Depondt, Guedon, Kebaili and Koka21 further recurrences, disease-free interval of less than six months,Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 close (5 mm or less) or positive margins,Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference White, Ford, Bush, Holsinger, Moore and Ghanem33 concurrent regional recurrence,Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Omura, Saito, Ando, Kobayashi, Ebihara and Yamasoba29 lymphovascular invasion,Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 alcohol abuse,Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24 and older age.Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28
Two studies considered the prevalence of p16 disease in oropharynx SCC and its relation to recurrence and overall survival.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Omura, Saito, Ando, Kobayashi, Ebihara and Yamasoba29 The article by Kim et al. was excluded as it was not possible to extract the p16 status of oropharyngeal SCC alone from their data, as they combined the p16 status from all head and neck subsites.Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23 Patel et al. found no statistically significant difference between local recurrence rates for p16- positive and negative patients.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 However, the increase in the number of p16-positive patients (n = 4) with distant metastasis, compared to p16-negative patients (n = 0), was statistically significant. Furthermore, in cases of p16-positive malignancies that recurred, all had treatment failure locally or in conjunction with regional and/or distant metastases, whereas the p16 negative group had treatment failure locally and/or regionally with no distant metastasis.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 The five-year recurrence-free survival rate for p16-positive patients was 21 per cent, compared with 12 per cent for p16-negative patients.
Discussion
Locoregional recurrences are the primary forms of failure following oropharyngeal SCC treatment. Despite advances in treatment modalities, surgery remains the main form of salvage treatment to improve patient survival. Goodwin published a meta-analysis reviewing survival following salvage surgery for recurrent upper aerodigestive tract SCCs.Reference Goodwin11 The review reported two- and five-year survival rates of 24.6 per cent and 26 per cent respectively for patients with pharyngeal SCC. Ours is the first systematic review to synthesise the best available evidence on survival outcomes following salvage surgery for recurrent oropharyngeal SCC. The review included 17 case seriesReference Aziz, Nyman and Edstrom17–Reference Gehanno, Depondt, Guedon, Kebaili and Koka21, Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23–Reference Röösli, Studer and Stoeckli32, Reference Shrewsbury, Adams, Duvall, Maisel and Haselow34 and 1 case–control studyReference White, Ford, Bush, Holsinger, Moore and Ghanem33 that met the inclusion and methodological quality criteria. Given the nature of surgical studies, large amounts of heterogeneity in methodological design and reporting of results existed between the included studies. These factors cause difficulty in the pooling of results for meta-analysis; thus the findings were presented in narrative form.
There has been a paradigm shift in the primary treatment of oropharyngeal SCC toward non-surgical treatment modalities. Despite evolution in the treatment modalities available, locoregional recurrences are a large source of morbidity and mortality. The vast majority of patients included in this systematic review were treated with primary RT, with or without adjuvant chemotherapy. Regardless of advances in surgical technology and techniques, there appears to have been a minimal change in long-term survival rates for patients undergoing salvage surgery for recurrent oropharyngeal SCC. Despite the apparent improvement in two-year overall survival of patients treated after 1990, there has been minimal change at five years. Bachar et al. demonstrated increased probability of death secondary to disease compared to other causes.Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18
The included studies demonstrated a range of factors associated with poor survival outcomes. The stage of oropharyngeal SCC at the time of recurrence has been associated with survival outcomes following salvage surgery, with overall stage III–IV, T3–4 or N2–3 disease associated with poorer survival outcomes.Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18, Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20, Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22, Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 Positive margins at salvage surgery have been correlated with poorer survival outcomes.Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference White, Ford, Bush, Holsinger, Moore and Ghanem33 Aggressive disease characterised by lymphovascular invasion, concurrent regional recurrences, and high histological grading with tongue base involvement have all been associated with poorer survival outcomes.Reference Gehanno, Depondt, Guedon, Kebaili and Koka21, Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Omura, Saito, Ando, Kobayashi, Ebihara and Yamasoba29 Furthermore, Culié et al. identified advanced tumour stages of T3 or greater to be associated with increased risk of recurrence.Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20
The presence of p16 staining as a surrogate marker for HPV is associated with improved survival outcomes.Reference Ang, Harris, Wheeler, Weber, Rosenthal and Nguyen-Tan35 Patel et al. found no significant difference in survival outcome following salvage surgery between HPV-positive and HPV-negative patients.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 The authors hypothesised that the similar survival outcomes may be a result of primary RT failure, representing a more aggressive p16-positive phenotype. These results are further supported by Sweeny et al., who found that patients in whom primary RT had failed had similar survival outcomes, regardless of HPV status.Reference Sweeny, Rosenthal, Clemons, Stevens, Cook McIntosh and Carroll36 The Omura et al. study consisted of a small cohort of oropharyngeal SCC patients with predominately p16-negative disease.Reference Omura, Saito, Ando, Kobayashi, Ebihara and Yamasoba29 Thus, no statistical conclusion could be drawn regarding the association of p16 status with recurrence and survival outcomes.
Further research is required to investigate the association between HPV status, patterns of recurrence and survival outcomes following salvage surgery. Studies included in this review focused on HPV status and patterns of failure after primary treatment. Patel et al. found only the p16-positive patients to have distant metastasis.Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25 The finding of increased distant recurrences in p16-positive patients was also found in the study by Huang et al.Reference Huang, Perez-Ordonez, Weinreb, Hope, Massey and Waldron37 They found that HPV-positive disease was more likely to disseminate to multiple organs and unusual sites, such as the lung, brain, skeletal muscle, and pericardial and intra-abdominal lymph nodes. Furthermore, distant recurrence occurred beyond two years following curative treatment, compared to the p16-negative patients where recurrence typically occurred within two years of treatment. It appears that p16 status affects the timing and type of recurrences in patients with oropharyngeal SCC following primary treatment. Fakhry et al. reported patterns of recurrence between p16-positive and p16-negative patients following primary chemoradiotherapy to be similar; however, two-year overall survival was significantly improved in the p16-positive group.Reference Fakhry, Zhang, Nguyen-Tan, Rosenthal, El-Naggar and Garden38
The mean time to recurrence following primary treatment was 15 months. The recurrence-free period following the primary treatment of oropharyngeal SCC was demonstrated to be a significant factor in survival. Kim et al. found that a recurrence-free period of six months or greater was associated with improved one-year survival following salvage surgery.Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23 Furthermore, Zafereo et al. found that 92 per cent of patients with no disease-free intervals developed recurrences, with overall survival rates of less than 20 per cent.Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 Additionally, 66.7 per cent of these patients developed a second recurrence within eight months of salvage surgery. These results indicate the need for vigilant follow up in the first 12 months post-operatively, with restaging scans if recurrences are detected.
The appropriate selection of patients for salvage surgery is crucial given the morbidity and mortality involved. It is thus important to identify factors that can predict outcomes after salvage surgery. Zafereo et al. concluded that favourable candidates for salvage surgery are: younger patients, with disease-free intervals following primary definitive treatment, and small recurrences for which it is possible to obtain negative margins, with the absence of neck recurrence.Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 Their definition of disease-free interval was a demonstrable complete response of the initial tumour to treatment, with later development of a second oropharyngeal SCC after a disease-free interval of six weeks.Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 Patients with poor general health, as identified by the Charlson Age-Comorbidity Index or American Society of Anesthesiologists’ physical status classification system, have been reported to have poorer survival following salvage treatment.Reference Culié, Benezery, Chamorey, Ettaiche, Fernandez and Poissonnet20, Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23 The combination of these previously discussed factors must be taken into account when deciding whether to offer salvage surgery and when counselling patients.
This systematic review found that salvage surgery for recurrent oropharyngeal SCC is associated with poor long-term survival. Despite these findings, salvage surgery appears to be the best chance of survival for patients with recurrent disease. The survival rates of salvage surgery patients were significantly higher than those for patients treated with palliative chemotherapy, re-irradiation or supportive care, with respective three-year overall survival rates of 32 per cent, 4 per cent and 5 per cent.Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28 Patient selection is paramount to the improved survival outcomes in this population. Salvage surgery could be offered to patients with favourable factors such as T1–2N0–1M0 disease, stage I or II disease, American Society of Anesthesiologists’ status 1 or 2, and non-drinkers, or those with a disease-free interval of six months or greater. Caution should be exercised when embarking on salvage surgery in patients with unfavourable factors as discussed above.
Post-operative complications following salvage surgery cause significant morbidity and mortality, affecting 17–78 per cent of patients. These range from mild wound infections to catastrophic carotid artery ruptures.Reference Bachar, Goh, Goldstein, O'Sullivan and Irish18–Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22, Reference Nichols, Kneuertz, Deschler, Lin, Emerick and Clark24, Reference Patel, Cohen, Givi, Dixon, Gilbert and Gullane25, Reference Zafereo, Hanasono, Rosenthal, Sturgis, Lewin and Roberts28, Reference Röösli, Studer and Stoeckli32, Reference White, Ford, Bush, Holsinger, Moore and Ghanem33 Current literature has shown that salvage surgery is associated with higher post-operative complications, particularly after chemoradiotherapy.Reference Lee, Shores and Weissler39 High-dose RT (over 60 Gy) is an important factor in locoregional flap or free-flap failure in head and neck reconstructive surgery, likely due to poor wound healing.Reference Kásler, Fodor, Oberna, Major, Polgár and Takácsi-Nagy22, Reference Benatar, Dassonville, Chamorey, Poissonnet, Ettaiche and Pierre40 Basso Ricci et al. found an increased incidence of fistulas when neck dissections were performed in conjunction with oropharyngeal resections.Reference Basso Ricci, Grandi and Salvatori19 Local and general complications were also closely correlated in patients with high levels of co-morbidities, including pulmonary disease, diabetes mellitus, myocardial infarction and peripheral vascular disease.Reference Kim, Kim, Albergotti, Choi, Kaplan and Abberbock23
Limitations of the current review are the lack of high-level evidence currently available. Despite large numbers of studies reviewing the efficacy of salvage surgery following oropharyngeal SCC recurrence, study quality is low because of methodological flaws. Heterogeneity and confounding factors are widespread across the included studies, and patients were treated with varying modalities of therapy for their primary malignancies. Furthermore, patients had different stages of disease recurrence. Studies should stratify patients according to their malignancy subsite, p16 status and overall disease stage, in order to decrease potential confounding factors. Ideally, the reporting of survival outcomes should be clearly documented and standardised to allow for future meta-analysis.
Conclusion
This review analysed the survival rates of patients treated with salvage surgery for recurrent oropharyngeal SCC. The two- and five-year overall survival rates of these patients were 52 per cent and 30 per cent respectively. There appears to have been improvement in 2-year overall survival rates over the past 30 years, possibly because of an association with HPV status. Standardised reporting of HPV status in treatment outcome studies for oropharyngeal SCC is required in the future to allow robust statistical analysis. Various factors associated with overall survival have been identified in this systematic review, which will assist clinicians in patient counselling and patient selection for salvage surgery.
Acknowledgement
The authors acknowledge Maureen Bell for her input and feedback regarding the search strategy.
Appendix 1. Search strategy
PubMed searched 17 March 2016: number of articles identified = 198
Search limits: English
oropharyngeal neoplasms[mh] OR oropharyngeal neoplasm*[tw] OR oropharyngeal squamous cell carcinoma*[tw] OR oropharyngeal SCC[tw] OR oropharyngeal cancer*[tw] OR oropharyngeal carcinoma[tw] OR oropharyngeal tumo*[tw] OR oropharynx cancer*[tw] OR oropharynx neoplasm*[tw] OR oropharynx carcinoma*[tw] OR oropharynx tumo*[tw] OR oropharynx squamous cell carcinoma*[tw] OR oropharynx SCC[tw] OR base of tongue[tw] OR tongue base[tw] OR BOT[tw] OR palatine tonsil*[mh] OR tonsil*[tw] OR palate, soft[mh] OR soft palate[tw]
AND
oropharyngeal neoplasms[mh] OR oropharyngeal neoplasm*[tw] OR oropharyngeal squamous cell carcinoma*[tw] OR oropharyngeal SCC[tw] OR oropharyngeal cancer*[tw] OR oropharyngeal carcinoma[tw] OR oropharyngeal tumo*[tw] OR oropharynx cancer*[tw] OR oropharynx neoplasm*[tw] OR oropharynx carcinoma*[tw] OR oropharynx tumo*[tw] OR oropharynx squamous cell carcinoma*[tw] OR oropharynx SCC[tw] OR base of tongue[tw] OR tongue base[tw] OR BOT[tw] OR palatine tonsil*[mh] OR tonsil*[tw] OR palate, soft[mh] OR soft palate[tw]
AND
Survival[mh] OR Surviv*[tw] OR Mortality[mh] OR Mortalit*[tw] OR Death*[tw] OR Prognosis[mh] OR Prognos*[tw] OR Treatment outcome[mh] OR Treatment outcome*[tw] OR Treatment outcome[mh] OR Outcome*[tw] OR Recurrence*[mh] OR Recurren*[tw] OR Relapse*[tw]
Embase searched 17 March 2016: number of articles identified = 315
Search limits: English
“oropharynx tumor”/syn OR “oropharynx tumor”/exp OR “oropharynx cancer”:ti,ab OR “oropharynx cancers”:ti,ab OR “oropharynx carcinoma”:ti,ab OR “oropharynx carcinomas”:ti,ab OR “oropharynx neoplasm”:ti,ab OR “oropharynx neoplasms”:ti,ab OR “oropharynx tumor”:ti,ab OR “oropharynx tumors”:ti,ab OR “oropharynx tumour”:ti,ab OR “oropharynx tumours”:ti,ab OR “oropharynx squamous cell carcinoma”:ti,ab OR “oropharynx squamous cell carcinomas”:ti,ab OR “oropharynx SCC”:ti,ab OR “oropharyngeal cancer”:ti,ab OR “oropharyngeal cancers”:ti,ab OR “oropharyngeal carcinoma”:ti,ab OR “oropharyngeal carcinomas”:ti,ab OR “oropharyngeal neoplasm”:ti,ab OR “oropharyngeal neoplasms”:ti,ab OR “oropharyngeal tumor”:ti,ab OR “oropharyngeal tumors”:ti,ab OR “oropharyngeal tumour”:ti,ab OR “oropharyngeal tumours”:ti,ab OR “oropharyngeal squamous cell carcinoma”:ti,ab OR “oropharyngeal squamous cell carcinomas”:ti,ab OR “oropharyngeal SCC”:ti,ab OR “base of tongue”:ti,ab OR “tongue base”:ti,ab OR BOT:ti,ab OR “palatine tonsil”:ti,ab OR “palatine tonsils”:ti,ab OR tonsil/syn OR tonsil/exp OR tonsil:ti,ab OR tonsils:ti,ab OR “soft palate”/syn OR “soft palate”/exp OR “soft palate”:ti,ab
AND
“Salvage therapy”/syn OR “Salvage therapy”/exp OR “Salvage therapy”:ti,ab OR “Salvage therapies”:ti,ab OR “Salvage surgery”:ti,ab OR “Salvage surgeries”:ti,ab OR “Salvage treatment”:ti,ab OR “Salvage treatments”:ti,ab OR “salvage procedure”:ti,ab OR “salvage procedures”:ti,ab OR Salvage:ti,ab
AND
Survival/syn OR Survival/exp OR Survival:ti,ab OR Survivor:ti,ab OR Survivors:ti,ab OR Surviving:ti,ab OR Surviving:ti,ab OR Mortality/syn OR Mortality/exp OR Mortality:ti,ab OR Mortalities:ti,ab OR Death/syn OR Death/exp OR Death:ti,ab OR Deaths:ti,ab OR Prognosis/syn OR Prognosis/exp OR Prognos*:ti,ab OR “treatment outcome”/syn OR “treatment outcome”/exp OR “treatment outcome”:ti,ab OR “treatment outcomes”:ti,ab OR Outcome*:ti,ab OR Recurrence/syn OR Recurrence/exp OR Recurrence:ti,ab OR Recurrences:ti,ab OR Recurrent:ti,ab OR Relapse:ti,ab OR Relapses:ti,ab
Cumulative Index to Nursing and Allied Health Literature searched 17 March 2016: number of articles identified = 30
Search limits: English
MH pharyngeal neoplasms OR TI oropharyngeal SCC OR AB oropharyngeal SCC OR TI oropharyngeal squamous cell carcinoma* OR AB oropharyngeal squamous cell carcinoma* OR TI oropharyngeal neoplasm* OR AB oropharyngeal neoplasm* OR TI oropharyngeal cancer* OR AB oropharyngeal cancer* OR TI oropharyngeal carcinoma* OR AB oropharyngeal carcinoma* OR TI oropharyngeal tumo* OR AB oropharyngeal tumo* OR TI oropharynx SCC OR AB oropharynx SCC OR TI oropharynx squamous cell carcinoma* OR AB oropharynx squamous cell carcinoma* OR TI oropharynx neoplasm* OR AB oropharynx neoplasm* OR TI oropharynx cancer* OR AB oropharynx cancer* OR TI oropharynx carcinoma* OR AB oropharynx carcinoma* OR TI oropharynx tumo* OR AB oropharynx tumo* OR TI base of tongue OR AB base of tongue OR TI tongue base OR AB tongue base OR TI BOT OR AB BOT OR MH tonsil OR TI tonsil* OR AB tonsil* OR MH palate,soft OR TI soft palate OR AB soft palate
AND
MH Salvage therapy OR TI salvage therap* OR AB salvage therap* OR TI salvage surger* OR AB salvage surger* OR TI salvage treatment* OR AB salvage treatment* OR TI salvage procedure* OR AB salvage procedure* OR TI salvage OR AB salvage
AND
MH Survival OR TI Surviv* OR AB Surviv* OR MH Mortality OR TI Mortlit* OR AB Mortlit* OR MH Death OR TI Death* OR AB Death* OR MH Prognosis OR TI Prognos* OR AB Prognos* OR MH Treatment outcome OR TI Treatment outcome* OR AB Treatment outcome* OR TI Outcome* OR AB Outcome* OR MH Recurrence OR TI Recurren* OR AB Recurren* OR TI Relapse* OR AB Relapse* OR
Cochrane Database of Systematic Reviews searched 17 March 2016: number of articles identified = 27
Search limits: English
oropharyngeal neoplasm* OR oropharyngeal squamous cell carcinoma* OR oropharyngeal SCC OR oropharyngeal cancer* OR oropharyngeal carcinoma OR oropharyngeal tumo* OR oropharynx cancer* OR oropharynx neoplasm* OR oropharynx carcinoma* OR oropharynx tumo* OR oropharynx squamous cell carcinoma* OR oropharynx SCC base of tongue OR tongue base OR BOT OR palatine tonsil* OR tonsil* OR palate, soft OR soft palate
AND
Salvage therap* OR Salvage surger* OR Salvage treatment* OR Salvage procedure* OR Salvage
AND
Surviv* OR Mortalit* OR Death* OR Prognos* OR Treatment outcome* OR Outcome* OR Recurren* OR Relapse*
Appendix 2. Critical appraisal instruments
Appendix 3. Data extraction tool
Appendix 4. Critical appraisal results
Critical appraisal of case series
Joanna Briggs Institute critical appraisal checklist of descriptive and case series
Critical appraisal of case–control study
Joanna Briggs Institute critical appraisal checklist for comparable cohort and case–control studies
