Oral squamous cell carcinoma (OSCC) is a significant public health problem. As the seventh most common cancer worldwide, it represents around 5% of all human malignancies.1-5 Lesions may involve any site of the oral mucosa and invade several continuous areas, with the most commonly affected areas being the tongue, the buccal/alveolar mucosa, and the floor of the mouth/ventral tongue.5-7 Its increasing incidence is mainly due to tobacco and alcohol consumption (responsible for approximately 75% of all OSCC cases).4,8,9 Association between HPV infection and the development of OSCC lesions has also been described; however, this mechanism is not yet fully understood, and better treatment responses occur in HPV-associated cancer lesions.10,11 Different lesion sites and patterns are associated with specific habits or medical conditions. Men and/or immunosuppressed patients have a higher risk of developing oral cancer.5,12
The OSCC incidence is reported to be higher in older patients (above 40 years old), although it has been increasing in females and young adults, accounting for up to 10% of OSCC cases.13,14 Survival rates for OSCC are poor due to its diagnosis being mostly made in advanced stages, and it is associated with high recurrence rates.1,4,15 The life quality of OSCC patients is difficult to measure and varies according to the lesion site. Speech, pain, appearance, chewing, and other factors are relevant domains to assess. To anticipate treatment impact, the tumor site, stage, and extent of mouth opening must be properly evaluated. After treatment, counseling and physical training can be provided to improve mouth opening, chewing, swallowing, and speech. Patients with late-stage OSCC and tongue lesions should also receive medication for pain control.14,16 Follow-up consultations should include an assessment of the patient's quality of life.
Early diagnosis is the key for therapeutic success.1,15 Early to moderate stages of OSCC are often treated surgically, which is the first-line treatment. However, the therapeutic approach may differ depending on the existence of positive lymph nodes and/or lymph nodes with metastasis extending beyond the lymph node capsule. Accordingly, radiotherapy with or without chemotherapy plays an import role.1,15 In advanced (stage IV) OSCC, multidisciplinary non-surgical therapeutic approaches are being used with increasing frequency to improve disease control, prolong survival, and maintain an acceptable quality of life for patients.1,4,8
Although conventional treatments (surgery, radiotherapy, and chemotherapy) have therapeutic effectiveness, recurrence rates for oral cancer are high, with the literature reporting recurrence rates higher than 50% in patients after primary treatment.15,17 Moreover, these treatments are associated with poor postoperative recovery, psychosocial impact, facial disfigurement, and functional disabilities, such as post-treatment xerostomia, mucositis, and fibrosis.15,18,19 Considering the frequent inefficacy of conventional treatment and the highly mutilating outcomes, alternative treatments for better management of this disease are needed.
Photodynamic therapy (PDT) uses photosensitizers–molecules which, when activated by light at an appropriate wavelength, lead to the generation of reactive oxygen species. These are cytotoxic and induce cancer cell death, damage tumor-associated vasculature (restricting oxygen and nutrient supplies), and activate an antitumor immune response.20 Photodynamic therapy relies on the use of photosensitizers with tumor selectivity, which are taken up by the cancer cells. After irradiation, these molecules become toxic, allowing the selective destruction of the tumor cells and limiting damage to healthy tissue.20,21
In the European Union, PDT is indicated for choroidal neovascularization associated with age-related macular degeneration and pathological myopia, mild to moderate actinic keratosis of the face and scalp, advanced cases of prostate adenocarcinoma, and head and neck squamous cell carcinoma.22 Additionally, PDT applications are described in pneumology for lung and pleural cancers; gynecology for high-grade cervical dysplastic lesions and menorrhagia; neurosurgery in glioblastomas or their recurrence; gastroenterology for esophageal cancers and cholangiocarcinoma; and in dermatology for superficial basal cell carcinomas and Bowen's disease.23
In the management of OSCC lesions, given that the oral cavity is readily accessible, PDT may be considered as a treatment option for topical therapy, primary treatment (PDT alone or combined treatment as neoadjuvant or adjuvant), in palliative treatment, and as a surveillance modality.19 However, the use of PDT in the oral cavity presents challenges related to the maintenance of uniform and precise illumination in the various regions of the mouth. In fact, variations may occur in the fluence rate, in the total light dose delivered, and in the angles of illumination. These occur mainly in anatomic regions with less accessibility (tonsils, posterior or base of the tongue, and oropharynx), and may represent an additional challenge in terms of treatment reproducibility, especially when multiple sessions are required.2,19 When evaluating the possibility of PDT, the depth of the lesion in the nearest accessible anatomical site must be taken into account as well as the presence of endogenous chromophores, which restrict the light supply into the lesion.19,20
Despite the described potential limitations of PDT, this therapy may represent an effective and more conservative treatment option in patients with recurrent OSCC. Among its advantages, PDT is a conservative treatment approach with few side effects. In the context of OSCC, PDT is a valuable option because of its excellent healing and cosmetic results, preservation of organ function, and the possibility of being performed before and after other treatments. Current evidence does not point to the use of PDT as a first-line option. However, PDT may be suitable for treating recurrent OSCC stages where conventional treatments are ineffective, as well as for patients without surgical eligibility.19 Thus, PDT may be a valuable option for patients with recurrent OSCC, and it is necessary to evaluate its effectiveness.
A preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews, and JBI Evidence Synthesis was conducted, and one systematic review on the topic was identified. This review analyzes PDT based on only one photosensitizer (Foscan) and dates back to 2013.22 The review has three important limitations. First, additional photosensitizers approved for clinical use were not considered, and these must be evaluated. Second, it does not differentiate between the use of PDT as the primary treatment and its use as the secondary treatment following other previously failed approaches. Third, as recognized by the authors of the review, the included studies did not provide enough evidence to determine the effectiveness of PDT in OSCC.22 Additionally, several other papers have been published since 2013.24-27
The objective of this review is to evaluate the effectiveness of PDT on the treatment response and survival of patients with recurrent OSCC.
What is the effectiveness of PDT on the treatment response and survival of patients with recurrent OSCC?
This review will consider studies that include patients (any age, gender, and geographic location) with clinical and histological diagnosis of all stages of OSCC treated with PDT, who underwent previous conventional treatments, such as surgery, radiotherapy, chemotherapy, or a combination of these therapies, and have been diagnosed with recurrent OSCC. Exclusion criteria include patients diagnosed with extra-OSCC, premalignant lesions, or PDT as first-line treatment.
This review will consider studies that evaluate patients with recurrent OSCC. All PDT regimens will be included; that is, all available photosensitizers (including Foscan, Photofrin, 5-ALA), all photosensitizer dosage and administration routes, all light fluences and drug-light intervals, and all follow-up periods.
This review will consider studies that compare the PDT intervention to no treatment or other treatments (surgery, radiotherapy, chemotherapy, or a combination of these therapies) in patients with recurrent OSCC.
This review will consider studies that include the following primary outcomes: response to treatment, assessed through remission of the lesion (complete, incomplete, no remission); recurrence of the lesion (recurrence, no recurrence); change in lesion size (no change, increase, decrease, changes in tumor dimension); alleviation of signs and symptoms (pain, edema); and patient survival (until one year, one to five years, more than five years). The secondary outcomes will be postoperative events; patient quality of life and satisfaction, evaluated through clinical findings (edema, cutaneous solar sensitivity/skin burns) and patients reports (pain, dysphagia, speech difficulties); and tumor necrosis, evaluated through histology (complete necrosis, partial necrosis, no necrosis detected).
Types of studies
This review will consider randomized and non-randomized clinical trials and observational studies (case-control, cohort, and cross-sectional) that focus on quantitative data.
The proposed systematic review will be conducted in accordance with the JBI methodology for systematic reviews of effectiveness.28 Recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) will be also considered.29 This systematic review protocol is registered in PROSPERO (CRD42020141075).
The search strategy will aim to locate both published and unpublished studies. An initial limited search of MEDLINE was undertaken to identify articles on the topic. The text words contained in the titles and abstracts of relevant articles, and the index terms used to describe the articles, were used to develop a full search strategy (see Appendix I) for MEDLINE (PubMed), Cochrane CENTRAL, Web of Science, and Embase. Sources of unpublished studies and gray literature to be searched include ClinicalTrials.gov. The search strategy, including all identified keywords and index terms, will be adapted for each included information source. The reference lists of all studies selected for critical appraisal will be screened for additional studies.
To be thorough, no limits will be employed in the search strategy. Studies published in English, French, Spanish, or Portuguese will be included.
Following the search, all identified citations will be collated and uploaded into EndNote v.X9.3.2 (Clarivate Analytics, PA, USA), and duplicates removed. Following a pilot test, titles and abstracts will be screened by two independent reviewers for assessment against the inclusion criteria. Potentially relevant studies will be retrieved in full and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia).30 The full text of selected citations will be assessed in detail against the inclusion criteria by two independent reviewers. Reasons for exclusion of full-text studies that do not meet the inclusion criteria will be recorded and reported in the systematic review. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion or with a third reviewer. The results of the search and study selection and inclusion process will be reported in full in the final systematic review and presented in a PRISMA flow diagram.31
Assessment of methodological quality
Eligible studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using standardized critical appraisal instruments from JBI for experimental and observational studies.28 Authors of papers will be contacted to request missing or additional data for clarification, where required. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. The results of critical appraisal will be reported in a table with accompanying narrative.
All studies, regardless of their methodological quality, will undergo data extraction and synthesis (where possible). The results of the critical evaluation will be incorporated into the discussion of the extracted data.
Data will be extracted from studies included in the review by two independent reviewers using the standardized JBI data extraction tool.28 The extracted data will include specific details about the populations (sample size, gender, age, characteristics of participants, OSCC grade), study methods, interventions (type of intervention and therapeutic protocol), and outcomes of significance to the review question (response to treatment, patient survival, postoperative events, patient quality of life and satisfaction, and tumor necrosis). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.
Studies will, where possible, be pooled with statistical meta-analysis using JBI SUMARI.30 Effect sizes will be expressed as either odds ratios (for dichotomous data) or weighted (or standardized) final post-intervention mean differences (for continuous data), and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard χ2 and I2 tests. Statistical analyses will be performed using the random effects model.32 Subgroup analyses will be conducted where there are sufficient data to investigate the effectiveness of different photosensitizers. Sensitivity analyses will be conducted to test decisions made regarding the impact of the inclusion of low-quality studies. Where statistical pooling is not possible, the findings will be presented in narrative format, including tables and figures to aid in data presentation, where appropriate.
If there are 10 or more studies included in a meta-analysis, a funnel plot will be generated using the Metafor package of R, v.4.0.3 (Free Software Foundation, Inc., Boston, USA) to assess publication bias. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed where appropriate.
Assessing certainty in the findings
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed33 and a Summary of Findings (SoF) will be created using GRADEpro GDT (McMaster University, ON, Canada). The SoF will include the following outcomes: remission of the lesion, recurrence of the lesion, lesion size, alleviation of signs and symptoms, patient survival, postoperative events, and tumor necrosis. The SoF will present the following information where appropriate: absolute risks for the treatment and control, estimates of relative risk, and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision, and risk of publication bias of the review results. These outcomes reported in the SoF will reflect PDT effectiveness in patients with recurrent OSCC.
CIBB is supported by National Funds via the Foundation for Science and Technology through the Strategic Projects UIDB/04539/2020 and UIDP/04539/2020.
Appendix I: Search strategy
1. Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 2008;87 (1):14–32.
2. Rosin FCP, Teixeira MG, Pelissari C, Corrêa L. Photodynamic therapy mediated by 5-aminolevulinic acid promotes the upregulation and modifies the intracellular expression of surveillance proteins in oral squamous cell carcinoma. Photochem Photobiol 2019;95 (2):635–643.
3. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009;45 (4–5):309–316.
4. Chow LQM. Head and neck cancer. N Engl J Med 2020;382 (1):60–72.
5. Alves AM, Correa MB, da Silva KD, de Araújo LMA, Vasconcelos ACU, Gomes APN, et al. Demographic and clinical profile of oral squamous cell carcinoma from a service-based population. Braz Dent J 2017;28 (3):301–306.
6. Pires FR, Ramos AB, de Oliveira JBC, Tavares AS, da Luz PSR, dos Santos TCRB. Oral squamous cell carcinoma: clinicopathological features from 346 cases from a single oral pathology service during an 8-year period. J Appl Oral Sci 2013;21 (5):460–467.
7. Perry BJ, Zammit AP, Lewandowski AW, Bashford JJ, Dragovic AS, Perry EJ, et al. Sites of origin of oral cavity cancer in nonsmokers vs smokers. JAMA Otolaryngol Neck Surg 2015;141 (1):5.
8. Hema Shree K, Ramani P, Sherlin H, Sukumaran G, Jeyaraj G, Don KR, et al. Saliva as a diagnostic tool in oral squamous cell carcinoma - a systematic review with meta analysis. Pathol Oncol Res 2019;25 (2):447–453.
9. Quintanilha NP, dos Santos Miranda Costa I, Freiman de Souza Ramos M, Campos de Oliveira Miguel N, Riemma Pierre MB. α-Bisabolol improves 5-aminolevulinic acid retention in buccal tissues: potential application in the photodynamic therapy of oral cancer. J Photochem Photobiol B Biol 2017;174:298–305.
10. Jiang S, Dong Y. Human papillomavirus and oral squamous cell carcinoma: a review of HPV-positive oral squamous cell carcinoma and possible strategies for future. Curr Probl Cancer 2017;41 (5):323–327.
11. Ramqvist T, Grün N, Dalianis T. Human papillomavirus and tonsillar and base of tongue cancer. Viruses 2015;7 (3):1332–1343.
12. Gharat SA, Momin M, Bhavsar C. Oral squamous cell carcinoma: current treatment strategies and nanotechnology-based approaches for prevention and therapy. Crit Rev Ther Drug Carr Syst 2016;33 (4):363–400.
13. Kapila SN, Natarajan S, Boaz K. A comparison of clinicopathological differences in oral squamous cell carcinoma in patients below and above 40 years of age. J Clin Diagn Res 2017;11 (9):ZC46–ZC50.
14. Abbas SA, Tariq MUU, Raheem A, Saeed J, Hashmi SS, Karim M, et al. Assessment of factors affecting quality of life in oral squamous cell carcinoma patients using University of Washington Quality of Life Questionnaire. Cureus 2019;11 (1):e390416.
15. Wang B, Zhang S, Yue K, Wang X-D. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer 2013;32 (11):614–618.
16. de Andrade FP, Antunes JLF, Durazzo MD. Evaluation of the quality of life of patients with oral cancer in Brazil. Braz Oral Res 2006;20 (4):290–296.
17. Cristaldi M, Mauceri R, Di Fede O, Giuliana G, Campisi G, Panzarella V. Salivary biomarkers for oral squamous cell carcinoma diagnosis and follow-up: current status and perspectives. Front Physiol 2019;10:1476.
18. Kligerman J, Lima RA, Soares JR, Prado L, Dias FL, Freitas EQ, et al. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Am J Surg 1994;168 (5):391–394.
19. Saini R, Lee N, Liu K, Poh C. Prospects in the application of photodynamic therapy in oral cancer and premalignant lesions. Cancers (Basel) 2016;8 (9):83.
20. Pereira NAM, Laranjo M, Pina J, Oliveira ASR, Ferreira JD, Sánchez-Sánchez C, et al. Advances on photodynamic therapy of melanoma through novel ring-fused 5, 15-diphenylchlorins. Eur J Med Chem 2018;146:395–408.
21. de Miguel GC, Abrantes AM, Laranjo M, Grizotto AYK, Camporeze B, Pereira JA, et al. A new therapeutic proposal for inoperable osteosarcoma: photodynamic therapy. Photodiagnosis Photodyn Ther 2018;21:79–85.
22. de Visscher SAHJ, Dijkstra PU, Tan IB, Roodenburg JLN, Witjes MJH. mTHPC mediated photodynamic therapy (PDT) of squamous cell carcinoma in the head and neck: a systematic review. Oral Oncol 2013;49 (3):192–210.
23. Verger A, Brandhonneur N, Molard Y, Cordier S, Kowouvi K, Amela-Cortes M, et al. From molecules to nanovectors: current state of the art and applications of photosensitizers in photodynamic therapy. Int J Pharm 2021;604:120763.
24. Hosokawa S, Takahashi G, Sugiyama K, Takebayashi S, Okamura J, Takizawa Y, et al. Porfimer sodium-mediated photodynamic therapy in patients with head and neck squamous cell carcinoma. Photodiagnosis Photodyn Ther 2020;29:101627.
25. Lambert A, Nees L, Nuyts S, Clement P, Meulemans J, Delaere P, et al. Photodynamic therapy as an alternative therapeutic tool in functionally inoperable oral and oropharyngeal carcinoma: a single tertiary center retrospective cohort analysis. Front Oncol 2021;11:518.
26. van Doeveren TEM, Karakullukçu MB, van Veen RLP, Lopez-Yurda M, Schreuder WH, Tan IB. Adjuvant photodynamic therapy in head and neck cancer after tumor-positive resection margins. Laryngoscope 2018;128 (3):657–663.
27. Hosokawa S, Takebayashi S, Takahashi G, Okamura J, Mineta H. Photodynamic therapy in patients with head and neck squamous cell carcinoma. Lasers Surg Med. 20185;50(5):420-6.
28. Tufanaru C, Munn Z, Aromataris E, Campbell J, Hopp L. Chapter 3: Systematic reviews of effectiveness. In: Aromataris E, Munn Z, editors. JBI Manual for Evidence Synthesis [internet]. Adelaide: JBI; 2020 [cited 2021 Aug 8]. Available from: https://synthesismanual.jbi.global
29. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4 (1):1.
30. Munn Z, Aromataris E, Tufanaru C, Stern C, Porritt K, Farrow J, et al. The development of software to support multiple systematic review types. Int J Evid Based Healthc 2019;17 (1):36–43.
31. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339 (21–1):b2535.
32. Tufanaru C, Munn Z, Stephenson M, Aromataris E. Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc 2015;13 (3):196–207.
33. Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. BMJ 2016;353:i2016.