It is well known that the best opportunity to cure patients with OSCC is through the delivery of fast and appropriate therapy at first presentations8–9. Theoretically speaking, management of “recurrence” after prior treatment is a challenging clinical situation, with decreased chances of cure by retreatment10. Although there is no standard criteria or consensus of a “true recurrent” OSCC, most still consider “recurrences” as those with similar pathological profiling, involving nearby anatomic structures (< 3 cm) and within 3 years of follow-up11. In literature, such “recurrences” were only divided by years, as either rapid or late recurrences, irrespective of detailed primary treatment10–12. As far as we are concerned, initial treatment, primary surgical margin and postsurgical symptom (pain) should all be taken into consideration when differentiating true “recurrent” and “residual” OSCCs, as some “recurrences” were in fact residual lesions (without intermittent remission of symptoms)13. These OSCCs become residual due more to improper initial treatment or insufficient resections, rather than to oncological aggressiveness of OSCCs. Determining the optimal retreatment regimens for this special group is very important, as most patients are extremely anxious about the likelihood of rapid and curative salvage re-resections14. According to the referral/admission report, the report of positive margins, along with the unrelieved painful symptoms, always encroached on the retreatment confidence in the primary treatment centers, given the fact that a high proportion (24.3%) of referrals were requested by patients. As occasionally encountered with these referrals, we tried to answer the question of whether these patients with residual OSCCs could still be rescued with SS-based treatment, as controversy for such decisions still exists.
Such residual OSCC problems were caused by a lot of factors, which however has long been under-evaluated. To a large extent, initial (primary) treatment status will negatively influence the survival outcomes16. Firstly, the factors of surgeons should not be downplayed. According to the referral reports and patients’ statements, the initial surgical treatment was carried out in some patients with unproven preoperative biopsies, which violated the principles of National Comprehensive Cancer Network (NCCN) guidelines17. Such condition was mostly due to false biopsy practice or lack of experiences for OSCC diagnosis. Besides, sometimes the variety of clinical presentations of OSCC and other premalignant oral lesions will also confuse the clinical diagnosis18. From a baseline diagnostic perspective, single or multiple incisional biopsies are required for large and non-homogenous lesions to confirm the OSCC diagnosis preoperatively18. The other mistake was the surgical completeness. Mismatch between primary OSCC stages and resection/reconstructive methods were abundant in our series, as some locally advanced lesions (n = 32, 31.3%) were even resected and reconstructed with direct closure or local flaps. Thus, the radicality of initial treatment was seriously questioned in these cases. In addition, a fairly large number of the cases in our study were with initial positive deep margins, implying possible flawed intraoperative resection regarding the tumor depth, which will finally compromise the treatment efficacies20, 21. Due to the terrible margin status in most patients, we advocate that en-bloc, or even compartment surgeries should be strongly recommended to ensure margin safety, particularly for adequate deep margins in advanced primary cases23, 24. Interestingly, even in some cases with primary early-stage OSCCs, residual lesions were still found in the tumor basins. We figured that such iatrogenic mistakes, which could have been avoided, were mostly due to unprepared preoperative surgical plans. For example, for cases with tongue cancers, the para-glossal resections should not be overly conversed for lingering fear of oro-cervical communications. The removal of sublingual gland and floor of mouth mucosa should also be advocated for a clear middle-zone eradication22–24. For cases with buccal cancers, especially those in the anteromedial buccal subsites, thorough-and-thorough resections should be attempted despite possible cosmetic disfigurement. For retromolar and lower buccal lesions, the resections of medial, sometimes lateral pterygoid muscles, marginal medial mandibulectomy should always be highlighted in those with clinically presentations of seemingly “early-stage” diseases, with true invasive fronts regarding the tumor depths25–27. Anatomically speaking, these parapharyngeal structures are adjacent, or in direct connection with the oral epithelial tissues, where improper surgical practice will result in positive margins26. Considering the treatment outcomes of these residual lesions, it is better to “err on the safe side” for extending the margins a bit wider, and to prepare intraoperative flap reconstructions, especially for some clinically T2-3 cases26, 27. Besides, the existence of cervical residual OSCCs were, in our opinion, partly due to unstandardized or improper resections or neck dissections, and to higher primary N grades which had also been cited in other studies as the reasons for regional (cervical) recurrences after neck dissections9, 28. We consent to the recent Clinical Practice Guideline issued by American Society of Clinical Oncology for establishing preliminary recommendations on the preliminary criteria of a high-quality neck dissection9. The anatomic hallmarks, levels and lest number of nodal specimens should also be emphasized for the best practice of surgical care for OSCC patients.
Apart from the surgical problems, as reflected in Table 2, other clinical factors should also be cautiously evaluated for avoiding treatment malpractice. Firstly, as is reflected in our series, 41.7% of the cases were with comorbidities, which might cause hesitations of aggressive surgical treatment from the patients’ and doctors’ perspectives29. Besides, the competencies of surgeons for such OSCC treatment should be assessed30, as 33.1% of the patients in our study received their initial treatment from junior consultants, or even surgeons from other non-relating specialties. Besides, patients who received surgical treatment from low-volume peripheral institutions tend to have improper or low-quality treatment practice in our series, with more chances of positive margins and lower likelihood of providing care adherent to guidelines31–32. However, such view was refuted by Eskander for conflicting evidence comparing the quality of care between high- and low-volume institutions33. For us, the ample experiences of treating OSCC on a regular basis made difference between different institutions and surgeons. In addition, the adverse survival relationships of “delays between biopsies and treatment” was consistent with the reports of others34. Due to such varied negligence in primary treatment, we call for strictly adhering to the treatment and diagnosis guidelines otherwise it may cause tremendous disaster to the patients.
For the treatment of resectable residual diseases, there were still unsettled controversies about the role and outcomes of SS, with vastly conflicting survival outcomes ranging from 8.3–62.5%6, 10, 36, 37. Most of these studies were with both residual and recurrent OSCC cases, which were further complicated by a higher proportion of patients with histories of prior radio- or radio-chemotherapies6, 37. We came up with the first report for the outcomes of immediate SS-based treatment against residual OSCCs, who were mostly radiation-naive. The answer of salvage likelihood for residual OSCCs was partially answered in our study, as the survival outcomes diversified among these patients. According to us, careful case selections for immediate SS should be emphasized based on both the initial and residual status. In the current study, patients with both smaller primary and residual OSCC sizes were mostly salvageable under a sound retreatment. However, for cases with larger residual disease burdens, the prognosis was generally unfavorable with a meager survival of 15.4%. The involvement of vital structures in residual OSCCs were also found to decrease the likelihood of rescue. As for the treatment designs, we found a slight advantage of survival for the SS group over AT-SS group. A stronger association was also found for the salvage resection and reconstruction extent, as most patients with wide margin re-resections and free-flap (including PMMF) reconstructions enjoyed better survival outcomes. Adjuvant radio- or radio-chemotherapy following SS should be considered in patients with residual OSCCs for a 10–20% survival advantage, which was also reported in other studies for recurrent OSCCs38, 39. As for other treatment combinations, the effects of targeted (EGFR or VEGF-based) therapies fell short of expectations as the trends of treatment outcomes reversed despite such added treatment regimens. We owed this phenomenon to both the treatment toxicities, and to the more advanced disease status of those who were inclined to receive such combinations. As far as we are concerned, routine postoperative radiotherapy or radio-chemotherapy was able to reach a similar, or even better outcome without the supplement of molecular targeted therapies, judging from our statistics.
Some limitations were inherent in the present study. Firstly, our results were obtained in a retrospective cohort in a single institution. Secondly, the treatment benefits for advanced residual cases were unable to summarize due to the small number in this investigation. Most patients were also irradiation-naïve in the primary treatment. In addition, the case selection for curative SS were quite subjective. Lastly, the effects of immunotherapies were elusive given the absence of such treatment at that time.