It is well known that the best opportunity to cure patients with OSCC is through the delivery of fast and appropriate therapy at first presentations [7, 15]. Theoretically speaking, management of “recurrence” after prior treatment is a challenging clinical situation, with decreased chances of cure by retreatment [16, 17]. 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-up [14]. In literature, such “recurrences” were only divided by years, as either rapid or late recurrences, irrespective of detailed previous primary treatment [14, 17,18,19]. As far as we are concerned, initial treatment modalities, prior surgical margin and postsurgical symptom (pain) should all be taken into consideration when differentiating true “recurrent” and “residual/persistent” OSCCs, as some “recurrences” were in fact residual/persistent lesions (with evidence of residual diseases or without intermittent remission of symptoms) [13]. We figure that 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-resections [14]. According to our referral/admission analysis, 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 actually requested by patients. As occasionally encountered with these referrals, we tried to answer the question of whether these patients with residual/persistent OSCCs could still be rescued with SS-based treatment, as controversy for such decisions still exists [11, 19, 20].
Such residual/persistent OSCC problems were caused by several factors, which however has long been under-evaluated. To a large extent, initial (primary) treatment status will negatively influence the survival outcomes [20]. 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) guidelines [21]. Such condition was mostly due to surgeons’ false biopsy practices or lack of experiences for early OSCC diagnoses. Besides, sometimes the variety of clinical presentations of OSCC, and possible concurrence of other premalignant oral lesions will also confuse or delay the early clinical diagnosis [22]. It has been widely acknowledged that an early and correct diagnosis is of utmost importance in reducing pretreatment intervals, providing standardized care and reducing mortality [22,23,24]. Mistakes of wrong or delayed OSCC diagnosis can be avoided with heighten awareness, as well as with extended use of novel techniques. Recent studies have also explored the possibility of having a set of biomarkers for assessment of suspected lesions, or differentiating between these benign and malignant oral lesions [25,26,27]. Despite high heterogeneity of these researches, it is interesting to find protein alterations in different genomic proteins during OSCC formation or development for possible early surgical interventions [26,27,28]. Apart from tissue genomic examinations, several non-invasive imaging OSCC diagnostic aids, such as fluorescence detection, can also be utilized to overcome the limits of routine oral examination. While not as informative as biopsy, these methods can aid in early identification of malignant transformation [29]. In addition, from a baseline diagnostic perspective, single or multiple incisional biopsies are also required for large and non-homogenous lesions to confirm the OSCC diagnosis preoperatively [18, 30]. The other mistake was the surgical completeness [31]. 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 efficacies [32,33,34]. Due to the terrible margin status in most of the 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 cases [35, 36]. 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 eradication [37]. 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, but true invasive fronts regarding the tumor depths [38]. Anatomically speaking, these parapharyngeal structures are adjacent, or in direct connection with the oral epithelial tissues, where improper surgical practice will result in positive margins [39]. 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 ycT2–3 cases [31, 32]. 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 [16, 40]. We consent to the recent Clinical Practice Guideline issued by American Society of Clinical Oncology for establishing preliminary recommendations on the criteria of a high-quality neck dissection [16]. The anatomic hallmarks, levels and lest number of nodal specimens should also be emphasized for the best practice of primary 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’ perspectives [41]. Besides, the competencies of surgeons for such OSCC treatment should be assessed [42], 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 practice in our series, with more chances of positive margins and lower likelihood of providing care adherent to guidelines [43, 44]. However, such view was refuted by Eskander for the conflicting evidence comparing the quality of care between high- and low-volume institutions [45]. For us, the ample experiences of treating OSCCs on a regular basis made difference between institutions and surgeons. In addition, the adverse survival relationships of “delays between biopsies and treatment” was consistent with the reports of others [46]. Due to such varied negligences in primary treatment, we call for strictly adhering to the treatment and diagnosis guidelines otherwise it may cause tremendous disaster to the patients. Conversely, improper management for OSCC will cause locoregional failure and even death [11,12,13]. The preoperative plan including surgical approach, reconstructive method and adjuvant therapy of oral cancer needs a multidisciplinary team to achieve the best clinical outcomes. A qualified and experienced surgical oncologist is prerequisite for the ultimate success of treatment. As revealed in our study, undertreatment from inexperienced surgical oncologist will lead to a dismal outcome and is not acceptable in the current standard of care.
For the treatment of resectable residual/persistent diseases, there were still unsettled controversies about the role and outcomes of SS, with vastly conflicting survival outcomes ranging from 8.3 to 62.5% [6, 10, 11, 47]. Most of these studies were with mingled residual/persistent and recurrent OSCC cases, within whom a higher proportion of patients were found with histories of prior radiotherapy or chemoradiation [4, 31, 47]. We came up with the first report for the outcomes of immediate SS-based treatment against residual/persistent OSCCs, who were mostly radiation-naive. The answer of salvage likelihood for residual/persistent OSCCs was partially answered in our study, as the survival outcomes diversified among these patients. According to us, careful case selections for 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 shown to decrease the likelihood of rescue. Within these, the extremely unfavorable outcome of 3 cases with carotid involvement and sacrifices alarmed us a possible contraindication when oncologic evidence of internal carotid artery wrapping was found. As for the treatment designs, we found a slight advantage of survival for the SS group over the 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 radiotherapy or chemoradiation following SS should be considered for patients with residual/persistent OSCCs, for a 10–20% survival advantage, reported in other studies [48, 49]. 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 treatment combinations. As far as we are concerned, routine postoperative radiotherapy or chemoradiation is able to reach a similar, or even better outcome without supplement of targeted therapies, judging from results in our statistics.
Undoubtedly, 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.
