Microvascular Reconstructions in Elderly Patients with Oral Squamous Cell Carcinoma—Too Old for Surgical Treatment?

Abstract

Study Design: Retrospective cohort study. Objective: A major risk factor for oral squamous cell carcinoma (OSCC) is advanced age. Ablative surgery combined with microvascular reconstruction has become routine for OSCC. Nevertheless, there is an interdisciplinary debate about the appropriateness of surgery combined with prolonged general anesthesia in the elderly. In the present study, the ablative and microvascular strategies in OSCC were evaluated in terms of oncologic safety and surgical morbidity in relation to age. Methods: A total of 345 patients with primary OSCC who underwent ablative tumor surgery and neck dissection according to the German national guideline for OSCC together with microvascular reconstruction from September 2010 to October 2017 were examined. General clinical data was analyzed descriptively with a special focus on perioperative morbidity of an elderly (≥70y) subgroup of 56 patients. Oncological outcome was estimated using Log Rank testing and Kaplan Meier plotting. Results: Estimated 5 year overall survival (OS) and disease-free survival (DFS) was 69.6% (≥70y) vs. 76.7% (<70y) and 62.9% (≥70y) vs. 78.2% (<70y) respectively with no significant difference between the 2 age groups. In multivariate cox regression, only initial stage of disease revealed significant impact on OS. Analysis of perioperative death/complications, flap loss, operation time, dependence on tracheostomy and hospitalization revealed no significant differences between the 2 groups. Conclusions: Tumor surgery including neck dissection in combination with primary microvascular reconstruction is a safe therapy in patients of advanced age. This results in excellent oncological outcome with no significant disadvantages in terms of perioperative morbidity, hospitalization or flap failure.

Introduction

Oral squamous cell carcinoma (OSCC) is subsumed with tumors originating from the epithelia of the larynx and pharynx under the term head and neck cancer (HNSCC).[1] Regarding our current knowledge of the distinct molecular landscape and distinct clinical course, subsites should be unraveled in detail.[1] Among these, tumors of the oral cavity account for up to 38% of all HNSCC.[2,3,4] Considering all cancer entities, OSCC incidence ranks on position 16 in global cancer analysis and is mainly caused by tobacco consumption and alcohol abuse.[5]

In Germany, a minimal decrease of incidence rates for patients with OSCC has been reported.[6] However, recent data from the Global Cancer Observatory (GCO) points to the relevance for decision-making in treatment of oral cancer in the elderly patients: By 2040, the incidence and corresponding mortality of OSCC is expected to increase by 40%.[7] Particularly alarming is the near doubling of the global incidence in older patients (>65) by 2045,[8] while only a 30% increase in incidence is predicted in patients <65.[9]

Surgical removal of the tumor with subsequent plastic coverage is still the therapeutic gold standard.[10,11] In advanced tumor stages, surgical treatment can be supplemented by adjuvant radio- or radiochemotherapy.[12] Depending on the reconstructive ladder, primary closure, local flaps, split-thickness skin grafts, regional flaps and microvascular flaps are technical options.[13] In addition to complete removal of the tumor, attention must also be paid to restoring and maintaining postoperative quality of life. The main goals of rehabilitation are to restore speech, chewing function[14] and swallowing. To achieve these goals, microvascular flaps are suitable, which contribute to optimal functional recovery thanks to a wide range of tissue types and a flap design adapted to the situation.[13] Nevertheless, studies indicate that older patients (>70) are more likely to choose a less aggressive treatment regimen than younger patients (<70) when it comes to treatment decisions.[15] With regard to the consensus-based macroscopic safety distance of 10 mm from the palpable tumor margin,[16] even in small tumors, the defect volume requires adequate coverage, which often cannot be achieved by primary closures or split-thickness skin grafts.[13] The application possibilities of local flaps are limited due to the often extensive defect size and the limited space available in the oral cavity.[13] Microvascular flaps, on the other hand, offer maximum freedom for safe oncologic resection due to the possibility of a variety of flap designs and a suitable choice of tissue.

In order to close the gap in the lack of evidence in surgery and reconstruction of elderly patients with oral squamous cell carcinoma, this study investigated a subgroup of OSCC patients aged 70 years or older with regard to oncological safety, surgical morbidity and hospitalization. In addition, it should be shown that chronological age alone should not be an exclusion criterion for adequate surgical treatment in advanced age.

Patients and Methods

Patients who underwent oncological surgery at the Department of Oral and Maxillofacial Surgery at Heidelberg University Hospital between 2010 and 2017 were screened. Prior illnesses and second tumors were not exclusion criteria. The prerequisite was that surgical tumor removal and reconstruction could be performed. Patients with a recurrence, previous radiotherapy of the tumor and carcinoma in situ were excluded. Retrospectively, the patients were divided into 2 groups based on their age (<70 years, >70 years), which were compared with each other. All patients underwent reconstruction with a microvascular flap (

Table 1. Clinical Data Regarding Perioperative Morbidity and Hospitalization.

).

Each patient gave written informed consent to participate. The study was approved by the ethics committee of the University of Heidelberg (Ethics vote: S-513/2017). The clinical data, histopathological parameters and follow-up were recorded using SAP Patient Management research (SAP, Walldorf, Germany). The findings and follow-up were recorded in an Excel-based electronic follow-up document to ensure standardized documentation for each patient. Treatment decisions were made in accordance with the German national guideline for OSCC. After histopathological confirmation of the tumor entity, staging was performed for all patients, including computed tomography of the head, neck and thoracic region. All patients underwent esophago-gastro-duodenal and bronchial endoscopy to rule out secondary malignancies. An interdisciplinary tumor board decision was made for all patients prior to treatment. The surgery included a tumor resection with a macroscopic safety margin of 10 mm and a level I-III neck dissection. In principle, several options can be considered for reconstruction: while primary defect coverage cannot usually be performed due to the large defects, reconstruction with local flaps is possible for small defects that affect less than a subunit of the head and neck region. Larger defects require coverage with free flaps,[17] which are characterized by their great versatility and good functional results.[18]

The selection of free flaps in our collective was based on the principle of “replace like with like”.

Bilateral neck dissection was performed in cases where carcinoma reached the midline (primarily anterior floor of the mouth) and in all patients with tongue cancers. All patients also received a post-operative interdisciplinary tumor board decision in terms of potential adjuvant therapy. As a rule, patients with close margin (0.5 mm distant from the tumor margin) or accumulation of histopathological risk factors (perineural invasion, lymph and blood vessel invasion) received adjuvant radiotherapy. During follow-up, patients were clinically examined every month in the first year and every 2 months during the second year. Subsequently, examination was performed every 3-6 months until the fifth post-operative year. Radio-logical aftercare included CT scan and sonography of the head and neck region every 3 months in alternation.

Statistics

Statistics were performed using SPSS® 27 (IBM, Armonk, NY, USA). Clinical data were analyzed descriptively regarding frequency, perioperative morbidity, flap loss, alcohol/nicotine abuse, mean surgery time, mean duration of tracheotomy, and mean hospitalization in days. Descriptive statistics were performed by independent t tests, ANOVA and the Mann–Whitney U test for mean comparisons of variables with 2 groupings. Chi-square and Fisher’s exact test were used to analyze categorical variables. Oncological outcome was estimated using Log Rank testing and Kaplan Meier plotting. Multivariate survival analysis was performed using the Cox proportional hazard regression model. Error probability of 5% was considered to be significant.

Results

In total, 345 patients with primary OSCC received surgery from 2010 until 2017. In all patients, microvascular flaps were used for optimal functional restoration. 56 of the 345 patients were aged 70 or older when they underwent surgery. The majority of the patients were male (66.7%), whereas 115 females (33.3%) were affected. In 194 cases, cancer was located at the lower jaw (56.2%), second leading anatomical region was the tongue in 88 patients (22.5%). Upper jaw was affected in 19 cases (5.5%), whereas soft palate was affected in 26 cases (7.5%). Buccal plane was affected in 18 patients (5.2%) (

Table 2. Correlation of Relevant Clinical Parameters Between the Groups.

). 107 patients (31.0%) received their diagnosis in stage I, 68 patients (19.7%) in stage II, 39 patients (11.3%) in stage III and the largest share with 131 patients (38%) received its diagnosis in stage IV. In the elderly group, half of the patients were diagnosed at stage IV. In the entire cohort, 169 individuals stated to be smokers (49.0%), whereas in the elderly group a significantly smaller number of 17 patients (30.0%) reported to be smokers (P = 0.004,t test; Table 2). The proportion of patients with alcohol abuse was also significantly lower in the elderly group (87 (25.0%) vs 7 (12.5%); P = 0.022,t test).

Treatment Comparison of Both Groups

A radial forearm flap (RFF) was primarily used for soft tissue reconstruction. In patients with contraindications for RFF or the requirement for high volume flaps, the anterolateral thigh flap (ALT) was used. In the edentulous alveolar process or upper jaw with expected bone invasion, fibula flap was applied. In patients with uncertain vascular supply of the lower extremity, scapula free flap was harvested instead (Table 1).

The proportional distribution of the selected grafts did not offer significant differences in both groups (age <70 years vs age ≥70 years) (Table 1). RFF was most frequently harvested for soft tissue replacement in both groups (61.2% (<70y) vs 50.0% (≥70y)) followed by ALT flaps (21.1% (<70y) vs 30.4% (≥70y)). For bone replacement, the fibula flap (9.0% (<70y) vs 12.5% (≥70y)) or the scapula flap 5.2% (<70y) vs 5.4% (≥70y)) were harvested (Figure 1).

Surgery Time. Time from incision to end of suturing was assessed electronically via SAP Patient Management research. There was no significant difference between the patients older, younger or at the age of 70 years (<70y: 431.35 min vs ≥70y: 408.07 min, P = 0.277, Chi,² Figure 2, Table 1).

Perioperative Morbidity and Hospital Stay

The patients who received tracheotomy were distributed almost equally in both groups (59.5% (<70y) vs 62.5% (≥70y); P = 0.678, ANOVA). Comparative analysis of graft loss rate showed no difference between both groups (9.0% (<70y) vs 8.9% (≥70y); P = 0.864, ANOVA). The stay on intensive care unit showed significant differences (4 days (<70y) vs 4.7 days (≥70y); P = 0.029, Chi²). The duration of dependency on tracheostomy did not show significant differences (16.4 days (<70y) vs 17.0 days (≥70y); P = 0.694 ANOVA, Figure 1, Table 1). The mean time of hospitalization was 20.3 days with a range from 3 to 121 days in the group of patients younger than 70 years. In the elderly group, the mean time of hospitalization was 22.6 days with a range from 9 to 51 days (P = 0.164, ANOVA, Figure 1, Table 1). The frequencies of perioperative deaths showed no differences between the 2 groups (2.1% (<70y) vs 1.8% (≥70y); P = 0.231, Chi,² Figure 2, Table 1).

Oncological Follow-Up

In the elderly group, 12 patients (21.4%) died during follow-up compared to 53 (18.9%) of the patients younger than 70 years. Cancer recurred in 13 elderly individuals (23.2%) vs 50 (17.9%) in the group of patients younger than 70 years (Table 1). Estimated overall survival after 5 years was 69.6% in the elderly group vs 76.7% in the group of patients younger than 70 years (P = 0.286, Log-Rank test). Estimated 5-year disease-free survival was 62.9% in the elderly group vs 78.2% in the group of patients younger than 70 years (P = 0.072, Log-Rank test). (Figure 3). In order to eliminate confounders, we adjusted overall survival and disease-free survival for stage of disease at diagnosis, age, sex and alcohol/nicotine abuse with Cox multivariate regression analysis. This adjustment resolved the trend for stage of disease at initial diagnosis and revealed tumor stage at diagnosis as the sole predictor at a statistically significant level for overall survival (P < 0.001 (OS),

Table 3. Disease Free and Overall Survival in Multivariate Cox Regression Analysis.

).

Discussion

Oral squamous cell carcinoma (OSCC) represents a major burden for the healthcare system worldwide. Despite recent molecular and immuno-oncological advances, surgical tumor removal remains the gold standard of treatment. As the global incidence of OSCC in older patients is expected to increase by approximately 100% by 2040, this is also likely to lead to a greater need for surgical treatment in this patient group.[19,20]

The debate as to whether surgical treatment should be the therapeutic method of choice for older patients or whether radiotherapy alone should be preferred due to the increased perioperative morbidity in older patients has not only been conducted in the field of oral and maxillofacial surgery.[21,22,23,24] However, a number of studies from various disciplines have demonstrated the superiority of surgical treatment over radiotherapy alone, even in older patients,[25,26,27,28,29] if their physical constitution allows it.

Postoperative morbidity is an important aspect, particularly in the case of extensive surgical procedures[30] in older patients. Compared to younger patients, this is increased in older patients.[31,32,33] It is reasonable to assume that a reduction in perioperative trauma could lead to improved postoperative morbidity. While no savings can be made in removing the tumor with a sufficient safety margin, the possibility of a sentinal lymph node biopsy (SLNB) instead of an elective neck dissection (END) should be considered in older patients with an early tumor stage and negative lymph nodes on imaging.

The meta-analysis by Liu et al, which examined 66 studies with a total of 3566 subjects in early tumor stages (T1 and T2), indicates that SLNB is equivalent to END in terms of the diagnostic predictive power of lymph node status.[34,35] SLN biopsy also does not appear to be inferior to END in terms of survival in patients with smaller tumors (T1 and T2).[36,37] Further studies also indicate that the functionality of the stomatognathic system and the post-operative quality of life after SLN biopsy exceed the results after END.[38] In addition, SLNB appears to be characterized by a lower complication rate compared to END.[37]

Especially in older patients in early tumor stages with negative neck findings on imaging, SLNB represents a possible alternative to classic END in order to achieve a reduction in postoperative morbidity. This is particularly the case if a transcervical approach is not required for guideline-compliant removal of the tumor or for defect reconstruction. However, an individual decision must always be made. This is because 20% of patients with OSCC have lymph node metastases even if the neck findings are negative clinically and on imaging.[39] A positive lymph node status is still a significant prognostic marker for poorer survival of patients with OSCC[40]: The high rate of occult metastases still warrants END. It must be weighed up in individual cooperation with the patient whether better postoperative morbidity and quality of life justify a possibly increased risk of shorter survival.

With regard to the radical nature of surgical treatment, there is another point to consider, particularly in older patients: Considering the target safety margin of 1 centimeter during tumor removal,[16] defects reach relevant volumes when a pure oncological resection is performed. Considering that half of the patients in the older group were only diagnosed at the highest stage of the disease, the need for adequate reconstruction becomes increasingly important. Furthermore, in reconstructive surgery, tissue should be replaced with parts that have a similar texture and volume (“like with like”) while ensuring lasting stability.

In principle, several options are available for defect reconstruction: The options of primary and secondary closure are generally ruled out due to the size of the defect. Following the reconstructive ladder, there is the option of treating the defect with split skin: Although large defects can be closed with split skin, there is the problem of insufficient graft volume, making functional reconstruction with split skin in the oral cavity rather difficult. Split skin is also rarely used in the face due to the moderate aesthetic results.

Local flaps are another option for reconstructing facial defects. However, for larger defects that affect more than half of an esthetic unit, these are not suitable from an esthetic and functional point of view.[41] Moreover, the often rather delicately designed flaps are usually not sufficient to adequately reconstruct large-volume effects and are therefore often not suitable for reconstructing patients with OSCC. All of these methods are feasible in principle, but carry the risk of functional impairment or an undesirable reduction in the safety margin for the surgeon.[42]

In older patients, some doctors therefore prefer primary coverage to microsurgical reconstruction. Before 2010, our internal strategy was to use local reconstructions and split-thickness skin grafts together with microvascular reconstructions. The retrospective analysis revealed a considerable rate of local recurrence.[43] The analysis revealed 122 OSCCs after clinical staging (safety level 2), of which 116 patients underwent local reconstruction. After pathologic staging (safety level 4), the 5-year disease-free survival of OSCC was 61.6%.[43] The results of the present study show that perioperative morbidity, ICU time and inpatient stay are the same in both groups. Therefore, the exclusion of elderly patients from standard radical therapy in combination with microvascular reconstruction should be limited to exceptional cases. It should be avoided that older patients are generally excluded from more complex treatment options because they are wrongly assumed to be frail.[24,44,45] Our results thus underline the statements of others who evaluate chronological age alone as an unreliable decision criterion for or against surgical therapy.[20,46,47] Our described results do not include information on quality of life and are limited due to the retrospective analysis. Nevertheless, the presented treatment strategy is consistently applied in almost all elderly patients in the analyzed period from 2010 to 2017 according to the German national guideline for OSCCs. Overall, consistent tumor ablation in combination with elective neck dissection and microvascular reconstruction in elderly patients with OSCC leads to a good oncological outcome with ideal function and low morbidity if the suitability for treatment is given. However, less traumatic surgical methods such as SLNB should also be considered for suitable patients in the future to minimize perioperative morbidity, especially in elderly patients.

Conclusion

In summary, it can be concluded from our results that age is not a predictor of surgical success in the treatment of patients with OSCC. Catchwords such as “being too old for surgery” no longer apply. If the patient is suitable for general anesthesia, surgery in combination with elective neck dissection and microvascular reconstruction is also recommended for older patients, whereby the option of a sentinal lymph node biopsy should also be considered.