Oral Oncol. 2015 Nov;51(11):e82-5.

The time interval between primary surgery and adjuvant therapy determines prognosis of oral squamous cell carcinomas.

Brockmeyer P1, Hemmerlein B2, Kruppa J3, Kauffmann P4, Tröltzsch M4, Schliephake H4, Gruber RM4.
  • 1Department of Oral and Maxillofacial Surgery, University Medical Centre Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany. Electronic address: ph.brockmeyer@gmail.com.
  • 2Department of Pathology, University Medical Centre Goettingen, Goettingen, Germany; Institute of Pathology, Helios Klinikum Krefeld, Krefeld, Germany.
  • 3Department of Medical Statistics, University Medical Centre Goettingen, Goettingen, Germany.
  • 4Department of Oral and Maxillofacial Surgery, University Medical Centre Goettingen, Goettingen, Germany.



This study aimed to investigate the influence of various parameters on the prognosis of patients suffering from primary oral squamous cell carcinoma (OSCC), in order to obtain valid criteria for therapeutic decisions in clinical practice. We analysed clinical and pathological parameters of 106 OSCC patients, and evaluated prognostic factors for the overall survival time (OS) and the incidence of first local recurrence (LR) using the random forest approach (RFA), competing risk regression (CRR), and Cox regression (CR). Among all investigated parameters a short time to recurrence (TTR; p=0.011), and an initial high T stage (p<0.001) revealed the highest impact on a poor OS by RFA and multivariate CR. The incidence of first LR was significantly influenced by a high age at primary diagnosis (p=0.041), alcohol (p=0.050) and nicotine abuse (p=0.002), and a high T stage (p=0.033), as shown by univariate CRR. A long interval between primary surgery and adjuvant therapy revealed the highest influence on the incidence of first LR by RFA. In conclusion, the interval between primary surgery and adjuvant therapy should be kept as short as possible, which is essential for a favourable outcome. Furthermore, we recommend a long period of short follow up intervals after primary therapy, because a short TTR characterises aggressive tumours with worse prognosis, and early identification of tumour relapse may improve the OS.



Despite improved diagnostic and treatment options, the mortality rate of patients suffering from oral squamous cell carcinomas (OSCC) remains high (1). The challenge is to select patients for individualised therapy. However, the search for biomarkers supporting individual therapy decisions has yet not been successful (2). Consequently, it is crucial to test the significance of clinicopathological routine parameters of patients with OSCC to improve the efficacy of current treatment protocols (3). In the recent investigation we showed that certain parameters affect the overall survival time (OS) and the incidence of first local recurrence (LR) in patients suffering from primary OSCC. The prognostic relevance of individual parameters for the clinical outcome is variable. Beside the classical regression models, we used the random forest approach (RFA) (4, 5) as a new statistical method to identify major risk factors for poor clinical outcome. The RFA can be used as a supplement to the classical Cox model to obtain more information about the relative importance of model covariates (6). We confirmed a significant impact of factors of the TNM classification system and of the AJCC criteria on the OS, as described by others (7-9). In contrast to previous studies (10), the anatomical location of primary OSCC did not significantly influence the OS or the incidence of first LR in the present investigation. The evaluation of the histopathological grade of differentiation is considered to be the gold standard for the prediction of the aggressiveness of OSCC in routine clinical practice (11). The present report failed to reveal a significant impact on tumour prognosis. Therefore, other factors beyond standard morphology could be of major importance. Biologically aggressive tumours recur rapidly within the first two years, leading to a poor outcome (12-14). Referring to a group of 515 patients with recurrence after radiotherapy, Stell found that TTR was the most significant factor for OS (14). Brandwein-Gensler and colleagues demonstrated that the resection status alone is an unsuitable predictor of local recurrence (15). In our series of 106 cases 98 cases had histologically confirmed tumour-free resection margins (R0). 55 of these 98 patients developed LR, of which 50 occurred in the first seven months after surgery. This could be due to inadequate intraoperative sampling of resection margins or discontinuous tumour spread. Furthermore, it was not possible to obtain precise data regarding the margin width. A different explanation could be that these tumours should not be regarded as a local recurrence, but as a metachronic second primary tumour. Our univariate analysis revealed a significant influence of a high age at primary diagnosis on the incidence of first LR. It seems as if an older age (7, 16) affects the clinical outcome more than gender (17, 18), body weight, and height. In line with previous reports (7, 9, 16), we found a significant influence of smoking on the incidence of first LR, which could influence the mortality in these patients. A long history of smoking, particularly of prognostically unfavourable level of smoking over years, could explain field cancerization and synchronic or metachronic tumour promotion of smoke-induced oral squamous epithelia at different sites as the genetic background of a metachronic second primary tumour. The level of genetic alteration and promotion of initiated oral epithelia could also explain the prognostically unfavourable effects of early LRs on OS. In a recent investigation, Katarkar et al. (19) used a micronucleus assay to detect DNA damages and concluded that this method could be used in the detection of premalignant conditions in oral mucosa. Gene expression profiling of primary OSCC samples, uninvolved oral mucosa from OSCC patients, and normal oral mucosae from patients without oral cancer (20), revealed that genetic dysregulation occurred in both cancer samples and corresponding uninvolved oral mucosal in 71 of the 167 probe sets. The dysregulation of 20 of the 71 probe sets was associated with progression-free survival (20). Moreover, patients with a history of low alcohol consumption per day showed a worse clinical outcome than those with high alcohol abuse in our univariate analysis. There was no evidence of a concurrent cause of death such as alcohol-induced liver failure. Therefore, high local oral mucosa concentration and blood concentration of alcohol may exert direct or indirect toxic effects on neoplastically initiated and promoted buccal epithelia, as already described for other cytotoxics (21).

In a biometric evaluation of 77 patients with OSCC, Kernohan et al. (22) compared patients treated with a combination of surgery and postoperative radiotherapy and patients treated with surgery or radiotherapy alone. They found an association between a poor OS and a combined treatment approach, which may be due to an advanced initial disease stage, aggressive tumour biology, and limited salvage options. In the recent analysis, a worse OS and the incidence of first LR were dependent on the period between surgery and the onset of adjuvant therapy. To date, there is no recommendation as to when an adjuvant therapy should commence. A delay in post-surgical adjuvant therapy of more than two months should be avoided to improve the clinical outcome in patients. Investigating the effect of the plastic reconstruction on the clinical outcome in patients with maxillary OSCC (23), Mucke and colleagues reported a better prognosis in patients treated with microvascular reconstruction (radial forearm flap, fibular flap, anterolateral thigh flap, iliac crest flap, combined flaps, perforator flap) compared to limited reconstruction (obturator, local reconstruction, cheek flap, split skin graft). In the present investigation, reconstructive modalities of different tumour stages were examined, whereupon patients treated with extensive plastic reconstruction (extensive tumour infiltration) showed a comparatively poor OS compared to those with limited reconstruction (slight tumour extension) in our univariate analysis. Notably, there are important differences between the extents of tumour infiltration, particularly between different stage T4 tumours. Depending on the localisation, e.g. skull base, different surgical and reconstructive strategies are necessary. Therefore, the question arises if the current TNM classification system allows for a sufficient discrimination, particularly of T4 stage OSCCs. 

In conclusion, a late onset of tumour disease and a history of severe nicotine abuse are associated with aggressive tumours with a high risk of tumour recurrence. The interval between surgery and adjuvant therapy should be kept as short as possible. We believe that an adjuvant therapy should commence within an interval of two months after primary surgery, because a delay in adjuvant therapy is associated with an increased risk of recurrence and poor OS. The close association between the time to recurrence and OS and missing biomarkers that predict the risk of LR or metachronic tumours support recommendations for monthly follow-up intervals over the first year to detect recurrence as early as possible and to keep the option open for a limited surgical local control.



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Dr. Phillipp Brockmeyer, MD, DMD

Department of Oral and Maxillofacial Surgery, University Medical Centre Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany.

E-mail address: ph.brockmeyer@gmail.com, orcid.org/0000-0003-3694-2828



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