Early recurrence is an adverse prognostic marker in patients with head and neck SCC [27]. However, the question as to whether the same applies to all malignancies of the head and neck area remains unanswered. First, tumors located at certain subsites (e.g., oropharynx and hypopharynx) rarely receive initial surgical treatment; in this scenario, only clinical staging can be implemented. Second, the correct endpoint for patients initially treated without surgery should be progression-free survival rather than recurrence-free survival. This is, to our knowledge, the first nationwide cohort study to investigate the impact of the relapse interval on the survival outcomes of patients with OCSCC after curative resection. Compared with patients with late relapse (> 330 days), those who relapsed early (≤ 330 days) had less favorable 5-year DSS and OS rates. After adjustment for potential confounders, early relapse was retained in the multivariable model as an independent adverse prognostic factor. Additionally, the adjusted AHRs for early relapse (3.24 for 5-year DSS and 3.91 for 5-year OS) were the highest among all of the independent RFs.
Since patients who relapsed early had a higher prevalence of several adverse prognostic markers compared with the late relapse group, PS matching was applied to minimize their potential confounding effect. The results – which were largely in line with those obtained from the original cohort – confirmed an adverse prognostic significance of early relapse for both survival endpoints (AHR for 5-year DSS: 3.10; AHR for 5-year OS: 3.32). Collectively, these data indicate that the occurrence of early relapse outweighed the prognostic impact of both traditional clinicopathological RFs and treatment modalities.
In the current study, pT4, pN3, Stage IV, poor differentiation, depth ≥ 10 mm, ENE, and distal relapse were associated with early relapse. These adverse prognostic factors are in accordance with those described in previous studies. Early relapsing tumors are expected to exhibit a more aggressive biological behavior and are characterized by higher maximum standardized uptake values on FDG-PET images [18].
In the original cohort, the early relapse group included a higher percentage of women compared with late relapse group (9.6% versus 4.3%, respectively, p < 0.0001, Table 1). Further analyses in relation to various clinicopathological RFs revealed no sex-related differences with respect to the following variables: pT status, pN status, p-Stage, DOI, margin status, treatment modality, and distant relapse. However, compared with men, women showed a higher number of tumors located in the tongue (61% versus 38%, p < 0.0001), age ≥ 65 years (31% versus 12%, p < 0.0001), poorly differentiated tumors (23% versus 14%, p = 0.0017), and ENE (37% versus 29%, p = 0.0273). Since betel nut chewing is endemic in our country, OCSCC is highly common. Notably, Taiwanese women with OCSCC rarely have a positive history of betel nut chewing. In this scenario, the male-to-female ratio for OCSCC in Taiwan is approximately 10-to-1 [28]. The higher prevalence of women in the early recurrence group may be explained by a preponderance of female patients harboring poorly differentiated tumors and ENE – two RFs related to tumor recurrence [29].
Smoking is a well-known risk factor for OCSCC. Of the five published studies focusing on clinical outcomes of patients with relapsing OCSCC (Table 4), only one study conducted by our group (Liao et al., 1996 − 2005) specifically focused on the effect of smoking. In our previous study [5], we found a trend towards a higher prevalence of preoperative smoking history in patients who relapsed early compared with the late relapse group (89% [143/161] versus 83% [92/111], respectively, p = 0.160). Conversely, in the current study, patients with late relapse showed a significantly higher prevalence of positive preoperative smoking history compared with the early relapse group (84% versus 79%, respectively, p = 0.0115, Table 1). The reasons underlying these discrepancies are unclear. However, smoking was not a significant risk factor for 5-year DSS and OS in patients with relapsing OCSCC both in our previous study [5] and in the current investigation. The question as to whether the association between late relapse and smoking is due to the development of recurrent disease versus second primary tumors merits comment. In this regard, it is noteworthy that patients in the late relapse group more commonly showed local recurrence compared with regional recurrence (Table 2). However, the results of this analysis should be interpreted cautiously because only the first recurrence event was collected in the TCRD registry. Consequently, the occurrence of neck relapse can be severely underestimated. Surgery remains the mainstay of treatment for first primary and recurrent OCSCC. However, the role of salvage surgery in patients who relapse early but do not harbor distant metastases is a matter of ongoing debate. We have previously shown that – in patients with OCSCC who relapsed early (optimal cutoff for relapse time: 10 months) – no survival differences were evident between treatment with salvage RT/CCRT versus salvage surgery [5]. However, in the late relapse group, treatment with surgery was associated with better outcomes compared with RT/CCRT [5].
Table 4
Published studies focusing on the clinical outcomes of patients with relapsing oral cavity cancer according to the relapse interval.
Authors (year of recruitment)
|
Relapse % (relapsed patients/original cohort), relapse by year
|
Exclusion based on the relapse interval
|
p-Stage I − II/III − IV (%)
|
Method used for determining the cutoff for the relapse interval
|
Definition of early/late relapse (number of patients)
|
Risk factors for survival outcomes (MVA)
|
Five-year survival rate (early/late relapse)
|
Liao et al. (current study)
(2011 − 2017)
|
16.9% (2327/13789),
84%/2-year
|
None
|
26%/74%
|
Cox proportional hazards model with spline
|
≤ 330 days (1630)
/>330 days (697).
After propensity score matching:
≤ 300 days (654)
/>300 days (654)
|
DSS: relapse interval, age, pN, p-Stage, DOI, distant relapse
OS: relapse interval, male sex, age, pT, pN, poor differentiation, DOI, distant relapse
|
Propensity score-
matched groups:
DSS: 30%/58%
(p < 0.0001);
OS: 22%/49%
(p < 0.0001)
|
Liao et al. [5]
(1996 − 2005)
|
28.5% (272/953)
nr
|
None
|
28%/72%
|
Kaplan-Meier
|
≤ 10 months (161)
/>10 months (111)
|
Early relapse (DSS/OS) a: p-Stage, poor differentiation, DOI, distant relapse
Late relapse (DSS/OS) a: pT, poor differentiation, ENE, distant relapse, neck recurrence
|
DSS: 14%/54%
(p < 0.0001),
OS: 12%/54%
(p < 0.0001)
|
Weckx et al. [6]
(2002 − 2015)
|
23% (159/691)
60%/2-year
|
< 6 weeks
|
43%/57%
|
Every 4 months followed by 1 year
|
1–4 months (11)
/5–8 months (32)
/9–12 months (15)
/13–24 months (37)
/>24 months (64)
|
OS: relapse interval, ENE, margins, salvage therapy
|
OS: 0%/40%/52%/49%
/87%
(p < 0.001)
|
Liu et al. [7]
(1995 − 2003)
|
50.5% (648/1282)
nr
|
< 6 months
|
54%/46%
|
ROC curve analysis
|
< 18 months (239)
/≥18 months (162)
|
OS: relapse interval, age, p-Stage
|
Survival after relapse:
28%/38% (p < 0.001)
|
Schwartz et al. [8]
(1956 − 1992)
|
28% (99/350)b
92%/3-year
|
≤ 3 months
|
47%/53%
|
nr
|
≤ 6 months (11)
/>6 months (27)
|
nr
|
Mean survival time:
20/54 months (p, nr)
|
Mucke et al. [9]
(1992 − 2006)
|
23.9% (185/773)
71%/3-year
|
≤ 6 months
|
46%/54%
|
ROC curve analysis
|
≤ 18 months (88)
/>18 months (97)
|
nr
|
Survival after relapse:
21%/42% (p = 0.03)
|
MVA multivariable analysis, DSS disease-specific survival, OS overall survival, ROC receiver operating characteristic, DOI depth of invasion, ENE extra-nodal extension, nr not reported |
a Identical prognostic factors for DSS and OS; b 38 of 99 patients met the inclusion criteria |
Another investigation reported that stage I − II primary tumors are generally candidates for salvage surgery, regardless of their initial treatment [8]. In our previous study, we found that patients with late relapse may benefit from salvage therapy, especially in presence of local recurrences. In the early relapse group, salvage therapy should be considered for cases with a primary tumor depth < 10 mm [5].
On univariate and multivariable analyses, Kernohan and coworkers [11] found that the initial use of a combined treatment (i.e., surgery plus adjuvant therapy) was associated with less favorable outcomes compared with monotherapies (i.e., surgery only or radiotherapy only). The results of our study indicated surgery plus adjuvant therapy (versus surgery alone) was a significant risk factor for 5-year DSS and OS in univariate analysis; however, this association did not persist after adjustment for potential confounders in multivariable analysis. This can be attributed to the high collinearity with other risk factors, including pN3 disease and early relapse (Table 3). In light of the lower survival rate observed in patients who received adjuvant therapy (versus those treated with surgery alone), we speculate that the use of salvage therapy in the adjuvant group would be lower than that of patients who received surgery as monotherapy. Unfortunately, the TCRD registry does not contain data on salvage treatment.
Herein, the 5-year OS rates of patients with and without relapsing tumors were 26% and 82%, respectively. In the former group, the 5-year OS rate was less favorable in presence of early relapse (15% versus 51% in the late relapse group). These findings are in accordance with those reported in our previous study [5]. After excision of the primary tumor with curative intent, the relapse rates of patients with OCSCC range between 23% and 51% (recurrent events within the first two years: 60 − 92%) [5–9, 11, 13, 30]. In the current study, the relapse rate was as low as 17%; additionally, 73% and 84% of all relapse events occurred within one and two years, respectively (Table 4). While the relapse rate in this study was lower than those reported in the published literature, the temporal distribution of the events was consistent with previous findings. Patients with higher p-Stage, a higher frequency of positive and close margins, and long-term follow-up performed at regular intervals may have higher relapse rates. While p-Stage III − IV disease was highly common in our cohort (74%), the low relapse rate (17%) may be explained by the irregular follow-up schedule (Table 4) – which was dependent on the nature of the data set. However, the large sample size may have partially offset this issue.
A limited number of studies have focused on the prognostic significance of the relapse interval in patients with OCSCC [5–11]. Most of them included patients with relapsing disease who were not stratified according to the treatment modality [5–9]; however, two studies were specifically carried out in patients who underwent salvage therapy [10–11]. On analyzing the relapse interval, some studies excluded patients who relapsed within certain time frames (e.g., from less than 6 weeks to 6 months) (6–9). In the current study, the number of days until relapse ranged between 14 and 2128 days. Because the TCRD includes an unequivocal code for never being disease-free (code: 70, Fig. 1), patients who relapsed very early (e.g., < 6 weeks) were not excluded. The interval between surgery and adjuvant radiotherapy was approximately 6 weeks. In presence of biologically aggressive tumor features (e.g., ENE), relapses may occur as early as 2 − 6 weeks after surgery. In a previous study from our group, a second FDG-PET scan before adjuvant treatment was clinically useful for early detection of residual/relapsing tumors [31]. Another investigation did not exclude patients with very early relapsing disease – which was defined as any tumor recurrence occurring be-tween surgical resection and the beginning of scheduled post-operative RT [32]. While the adverse prognostic significance of early recurrence is in line with the current literature, the optimal cutoff for the relapse interval was not consistent across studies [6–9]; these discrepancies may be related to different study designs, patient characteristics, and statistical methodology.
On analyzing the prognostic impact of different RFs, we found that ENE – which has a decisive influence on survival outcomes in OCSCC – did not retain its independent predictive value in patients who relapsed. This surprising finding may be related to the collinearity between the presence of ENE and pN3 disease. Additionally, the prognostic impact of margin status in our patients with relapsing disease was limited. While tumor margins are a significant prognostic driver for local control and distant metastases, their impact on neck control is limited [1]. In general, we found that patients who relapsed early had a higher burden of clinicopathological RFs compared with the late relapse group. In this scenario, a thorough follow-up schedule aimed at an early detection of relapsing disease should be recommended for all patients who harbor baseline RFs.
The site of tumor relapse was found to be a key prognostic determinant; specifically, the presence of relapsing disease at distant sites was associated with dismal outcomes (5-year OS rate in the current study: 4%; Supplementary Fig. 1). The question as to whether an early detection of distant metastases may improve the outcomes of patients with OCSCC remains unanswered. We have previously shown that a second FDG-PET scan before adjuvant treatment may detect distant relapses in up to 10% of patients with OCSCC and ENE [31]. In addition, patients with known locoregional relapses should be strictly monitored for the potential occurrence of relapsing disease at distant sites (16). At 3, 6, 9, and 12 post-treatment months, high-risk patients should undergo CT/MRI and/or FDG-PET imaging of the head and neck, thorax, and abdomen with the goal of detecting recurrent lesions [16]. Neck ultrasound, fine needle cytology, or core needle pathology (when necessary) in combination with CT/MRI/FDG PET imaging can also be helpful for detecting recurrent disease.