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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 3-9

Intensification of adjuvant treatment in early oral cancers

Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission08-Jun-2021
Date of Decision08-Jun-2021
Date of Acceptance09-Jun-2021
Date of Web Publication23-Jul-2021

Correspondence Address:
Prof. Sarbani Ghosh Laskar
Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aort.aort_15_21

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Combined modality therapy with surgery followed by appropriate adjuvant treatment with radiation therapy with or without concurrent chemotherapy based on risk factors is the standard of care for locally advanced cancers. However, in early cancers with unfavorable features, treatment policies vary across different centers, with decisions often based upon the treating oncologist's clinical discretion and institutional practice. In this review article, we intend to discuss the existing literature on the role of adjuvant treatment intensification in early node-negative and single node-positive oral cavity cancers.

Keywords: Adjuvant treatment, intensification, oral cancer

How to cite this article:
Kumar A, Sinha S, Laskar SG. Intensification of adjuvant treatment in early oral cancers. Ann Oncol Res Ther 2021;1:3-9

How to cite this URL:
Kumar A, Sinha S, Laskar SG. Intensification of adjuvant treatment in early oral cancers. Ann Oncol Res Ther [serial online] 2021 [cited 2022 May 23];1:3-9. Available from: http://www.aort.com/text.asp?2021/1/1/3/322155

  Introduction Top

Oral cavity cancers form a significant proportion of head-and-neck malignancies worldwide, with over 3 lakh new cases diagnosed yearly.[1] In India, oral cavity cancer is the second most common cancer and the third most common cause of cancer mortality.[2] Single modality treatment with surgery is preferred for early cancers. Radical radiotherapy (RT) has a role in select cases where surgery can lead to significant morbidity or in medically inoperable patients.[3] Following surgery, adjuvant treatment with radiation therapy ± concurrent chemotherapy is routinely practiced for locally advanced cancers of the oral cavity (Stage III/IV) based on risk stratification.[4],[5] The doses for adjuvant radiation therapy were adopted depending upon the patterns of local failure.[6],[7] The addition of chemotherapy in the presence of high-risk features such as perinodal extension and positive margins showed an absolute overall survival (OS) benefit of 13% in the EORTC 22931 trial while only longer disease-free survival (DFS) as demonstrated in the RTOG 9501 trial.[8],[9],[10],[11]

Intensification of adjuvant treatment has been a matter of debate even in locally advanced tumors. In a retrospective study by Trifiletti et al. in 10,870 patients with multiple positive nodes with negative surgical margins and no extracapsular extension, chemoradiation was associated with improved OS compared to RT alone (hazard ratio [HR], 0.90; P < 0.001). Chemoradiation (CRT) was associated with a higher OS benefit in patients with 2–4 nodes (3-year OS, 71.0% vs. 66.6%; HR, 0.84; 95% confidence interval [CI], 0.78–0.91; P < 0.001) and with >5 nodes (3-year OS, 62.9% vs. 58.9%; HR, 0.88; 95% CI, 0.78–0.987; P = 0.029).[12]

In a large randomized controlled trial of 900 patients by Ghosh Laskar et al., intensification of adjuvant treatment with concurrent chemoradiation or accelerated radiation therapy did not improve locoregional control (LRC) or OS in locally advanced Stage III/IV oral cavity squamous cell cancers.[13] Hence, the addition of chemotherapy in the presence of multiple lymph node involvements without extranodal extension remains a matter of contention. This can be a potential area of research in the future.

The issue of intensification of therapy in the presence of a combination of adverse features other than positive cut margins or extranodal extension also remains unresolved. The results of the RTOG 0920 are much awaited to understand if further intensification of therapy is warranted in patients who have these intermediate-risk features.

  Early Node-Negative Tumors Top

The ideal treatment of early node-negative oral cancers and the added benefit of neck dissection has been a long-drawn debate with conflicting results from different studies, including data from prospective trials.[14],[15],[16],[17],[18] A large randomized trial conducted at Tata Memorial Centre by D'Cruz et al. in 596 patients of node-negative oral cancers showed a 12.5% absolute benefit in OS and a 23.6% DFS benefit in elective neck dissection in comparison to performing a therapeutic neck dissection at the time of nodal relapse.[19] This study also revealed a marked increase in lymph node positivity with an increase in depth of invasion (DOI) from 3 mm (5.6%) to 4 mm (16.9%).

The lymph node count in a neck dissection is a quality metric that can predict survival.[20] An adequate ipsilateral elective neck dissection should include at least 18 lymph nodes.[21] In a retrospective study from Taiwan of 126 oral cavity cancer patients who underwent wide excision and neck dissection, a lower survival rate was seen when the total number of neck nodes examined was <37 with poor differentiation or nerve invasion.[22] The American Society of Clinical Oncology clinical practice guidelines also recommend at least 18 lymph nodes in ipsilateral levels, Ia, Ib, II, and III for a clinically N0 neck to label it an adequate neck dissection.[23]

  Role of Sentinel Node Biopsy Top

Elective nodal dissection (END) in the clinically negative neck may be an overtreatment in a significant proportion of patients with head-and-neck cancers. Shoulder dysfunction, cosmetic deformity, and cutaneous paresthesia are certain recognized complications of neck dissection that can affect the long-term quality of life.[24],[25] Sentinel lymph node biopsy (SLNB) has emerged as an accurate staging procedure in the clinically node-negative neck.[26] A diagnostic meta-analysis by Govers et al. in 847 patients from 21 studies reported an overall sensitivity of 93% in oral cancers.[27] In a study by Chaturvedi et al. comparing the diagnostic accuracy of ultrasound-guided fine-needle aspiration cytology and sentinel node biopsy (SNB) in the staging of clinically negative neck in T1 and T2 oral cancers, SNB emerged as the more accurate staging tool for detection of occult neck metastases.[28] SNB is not used frequently in practice despite the high specificity and accuracy since the procedure is time-consuming, invasive, and requires multidisciplinary expertise. However, with infrastructure and expertise, SNB can be an effective alternative to END in early, node-negative oral cancer.

A recent advance in head-and-neck cancers is the role of single-photon emission computed tomography (SPECT)-guided elective nodal irradiation (ENI). In a prospective study of 44 patients who underwent SLN mapping with SPECT followed by prophylactic nodal irradiation, only one patient experienced a regional relapse in a nonirradiated area after a median follow-up of 46 months.[29] Another recent trial of 50 patients treated with SPECT-guided ENI also demonstrated a low risk of contralateral regional failure with a significant reduction of dysphagia, feeding tube placement, and late xerostomia.[30] The encouraging results from these studies and more evidence from ongoing trials can make this approach a potential practice-changing one in the future.

  Importance of Cut Margins Top

Surgical cut margin status is an important prognostic factor for local recurrence in oral cancers. Clear margins are usually obtained in 50%–80% of resected specimens. Tumor margins shrink significantly after formalin fixation by about 25%.[31],[32],[33] Intraoperative assessment of margins, specimen orientation, and margin sampling require close cooperation between the surgeon and pathologist.[34] An adequate surgical resection should have at least 5 mm margins around the tumor.[35] A significant improvement in local relapse-free survival (LRFS) was identified with cut margins up to 7 mm according to a retrospective study in 602 patients; however, no effect was seen beyond 7 mm.[36] No further treatment may be warranted with a negative margin in an early-stage tumor, especially if the neck dissection yields no involved nodes, in the absence of any risk features. In a retrospective study to redefine the close surgical margins in early squamous cell carcinoma (SCC) of the tongue, LRFS was significantly affected when margins were ≤2.2 mm. There was no difference between margins from 2.3 to 5 mm and more than 5 mm.[37]

An international collaborative study of 1257 patients with T1-2N0M0 oral cancers showed that the 5-year OS rate was 80% for patients with clear margins, 52% for patients with close margins (<5 mm), and 63% for patients with positive margins (P < 0.0001). Close margins had more than a 2-fold risk of recurrence.[38] Twenty-eight percent of the patients received adjuvant treatment. In a subgroup analysis, adjuvant treatment was associated with a significantly lower HR for all outcome measures. In a subset multivariate analysis in patients with close/positive margins treated with adjuvant RT, OS and disease-specific survival (DSS) were significantly better. In a meta-analysis by Bulbul et al., it was noted that revisions to obtain clear margins (R0) in initially involved margins (R1) had worse LRFS compared to the upfront R0 group (HR = 2.897, P < 0.001).[39] In another retrospective review of 268 patients, it was found that adjuvant RT decreased local recurrence in patients with initially positive margins cleared to negative margins.[40]

With the available literature, the addition of adjuvant RT is beneficial in early tumors with close/positive margins and also in cases where the initial frozen section margins are positive. Hence, every attempt must be made to achieve a negative margin and selection of cases based on the ability to do so.

  Depth of Invasion Top

From multiple studies, it is understood that DOI has a role in predicting neck nodal metastasis. The incidence of nodal metastasis was higher when DOI was >5 mm.[41],[42],[43],[44] In a retrospective analysis of 3149 patients conducted by the International Consortium for Outcome Research in Head and Neck Cancer from 11 centers worldwide, a significant difference in outcomes was noticed between T1 tumors with DOI >5 mm and T2 through T4 tumors. The authors also proposed to include DOI in future versions of AJCC based on the results of this study.

  The Updated AJCC 8th Edition Top

The 8th edition of AJCC staging incorporated various changes based on the clinical and biological behavior of head-and-neck cancers.[45] The inclusion of DOI in T staging and extranodal extension in N staging were the highlights in the current edition. DOI assesses the invasiveness of a carcinoma, regardless of any exophytic component.

The use of DOI instead of tumor thickness has predominantly resulted in upstaging of the T category compared to the previous edition.[46] However, DOI has been included only in the pathological T staging.[47] In early-stage oral cancers, the 8th edition has been reported to be better in predicting prognosis.[48],[49],[50] In oral cancers, and especially in cancers of the tongue, it would be ideal for providing adjuvant treatment with increasing DOI and especially when there is a combination of other associated adverse features. However, controversy still exists on the cutoff beyond what DOI should adjuvant therapy be considered, in the absence of other adverse features.

  Metastasis to a Single Lymph Node Top

In cases where there is metastasis to only one ipsilateral node in the absence of other risk factors such as positive margins, extracapsular invasion, perineural invasion (PNI), or lymphovascular invasion (LVI), it is unclear if adjuvant radiation therapy can improve survival outcomes. NCCN guidelines recommend adjuvant RT with one positive node and without adverse features (Category 2A).[51] In a SEER database from 2004 to 2013 of 746 patients with T1-T2N1 oral cavity squamous cell carcinoma (OCSCC), it was seen that adjuvant RT improves survival outcomes in both T1 and T2 tumors with a single positive lymph node. However, the magnitude of benefit was higher in patients with T2 cancers. The percentage utilization for adjuvant RT also decreased significantly from 71% to 55% in T1N1 tumors.[52]

  Perineural Invasion Top

PNI is defined as tumor cells within any layer of the nerve sheath or tumor in the perineural space that involves at least one-third of the nerve circumference.[53] The role of PNI as a poor prognostic factor as an indication for adjuvant treatment has conflicting results.

In a study of 307 patients with T1-T2 OSCC by Tai et al., PNI predicted for neck metastasis (P < 0.001, HR: 3.36), neck recurrence (P < 0.001, HR: 4.25), and DSS (P = 0.027, HR: 2.08). Elective neck dissection resulted in a significantly better 5-year DSS in clinically node-negative patients with PNI-positive tumors (P = 0.0071).[54] In another retrospective review of 322 patients by Thiagarajan et al., a statistically significant reduction was seen in relapse-free survival in the presence of PNI (60 months vs. 26 months, P = 0.027).[55]

The use of adjuvant RT in the presence of PNI remains controversial. In an extensive retrospective analysis by Nair et al. in 1524 patients of OCSCC, PNI was seen in 20.3% of tongue cancers (odds ratio [OR]: 2.43). The presence of PNI significantly influenced DFS and OS. PNI resulted in a higher number of recurrences and mortality (HR: 2.79 for DFS; HR: 2.54 for OS) in early node-negative oral cancers. The use of adjuvant radiation in such patients demonstrated an improvement in survival (P = 0.022).[56]

A retrospective study of 442 patients with early-stage oral cavity cancers, PNI, and LVI did not show significance for disease control and OS for early-stage OCSCC.[57] A single-institution study that analyzed two subgroups of 39 patients of OSCC (one with PNI and one without PNI, all patients having negative margins, no LVI, p N0-1 disease without Extracapsular spread [ECS]) showed that PNI was associated with an increased risk of lymph node metastasis and regional recurrence. The addition of adjuvant radiation therapy did not improve outcomes.[58]

In a prospective randomized trial of T1-T2N0 tongue SCC conducted across 221 patients, between elective neck dissection and observation, PNI was identified as an independent factor for neck nodal relapse.[59] It was also noted that END could not improve outcomes in such patients, thus questioning the role of treatment intensification.[60] It was noted that PNI in tongue cancers is associated with a worse DSS, with distant recurrence as the most common pattern of failure.

Another factor considered along with PNI is the focus density which is defined as the total number of foci of PNI identified, divided by the number of tumor sections reviewed by the pathologist. Any patient with >1 focus per section was considered to have a high focus density. In a study by Cracchiolo et al. analyzing the recurrence patterns in oral tongue cancer with PNI, distant recurrence was identified as the most common pattern of failure. Worse DRFS was seen in high PNI focus density. This may be a subset that can benefit with the intensification of local treatment.

Despite this, the importance of PNI by itself when adequate neck dissection has been done and in the absence of other adverse features remains open. The role of adjuvant RT in this situation also needs to be evaluated.

  Lymphovascular Invasion/Lymphovascular Emboli Top

LVI is defined as the presence of tumor cells within an endothelial-lined space. Penetration of tumor cells into lymphovascular spaces through the endothelial cell layer has a role in tumor metastasis. The presence of LVI in oral cancers is an adverse risk factor associated with a poor prognosis.[61],[62] However, there is no consensus regarding the role of LVI as a significant prognostic factor in oral cancers.

Close et al. in one of the first reports on LVI demonstrated an association between LVI and nodal metastasis.[63] In another study by Cassidy et al. in 180 patients with node-negative oral cancers, the presence of LVSI showed worse LRC (OR, 0.06; P < 0.01). Three-year LRC rates were lower for patients with LVSI (38.8%) than those without LVSI (81.9%). Three-year OS was also significantly lower in patients with LVSI (71.3%) than those without LVSI (90.3%).[64]

In a recent meta-analysis from 36 studies involving 17,109 patients with OSCC, positive LVI was significantly associated with lymph nodal metastases and worse survival in patients with OSCC.[65] LVI predicted the occurrence of lymphatic metastasis in 9 studies that reported early-stage OSCC. However, the use of adjuvant treatment in LVI-positive patients remains controversial, underlining the need for more robust evidence.

  Histological Grade, Differentiation, and Worst Pattern of Invasion Top

Although it is important to achieve negative margins during surgical resection, one of the other important prognostic factors is the histological grade of the tumor. In an ambispective study, patients were divided into four groups based on margin status. On analysis, worst pattern of invasion (WPOI) was significantly associated with local recurrence (P = 0.015) and OS (P < 0.001). PNI involving large nerves (>1 mm) was associated with LR (P = 0.005) and OS (P = 0.039).[66] Further classification was done as per histological risk features including PNI, WPOI, and lymphocytic response to low, intermediate, and high risks. The addition of adjuvant radiation therapy was associated with increased local DFS for high-risk patients only (P = 0.02).

In another retrospective study of 2535 patients of OCSCC, advanced tumor stage was seen in 23.9%, 44.0%, and 55.1% of patients with Grades 1–3 OSCC, respectively. Lymph nodal metastasis was seen in 45.9% of Grade 3 patients. Significant differences in survival were seen with different grades of tumor. In a study of 387 patients of oral cavity SCC and pT1-2N0 disease, poor differentiation and pathologic tumor depth of 4 mm resulted in lower 5-year neck control, DFS, DSS, and OS.[67] Poor differentiation is an important factor associated with inferior outcomes and may warrant intensification of treatment.[68]

  Risk Assessment Models Top

In a validation study of the risk models in 305 patients from 3 institutions, risk category predicted for time to disease progression, locoregional recurrence, and OS. Compared to low risk and intermediate risk, high-risk status was significantly associated with decreased time to disease progression.[69] It would be useful to develop/validate risk assessment models to identify patients of early-stage cancers who are at a high risk of disease progression and in whom adjuvant treatment intensification may be beneficial. In a study of 233 cases of T1–T2 tongue cancers in 5 institutions from Finland, DOI and tumor budding were associated with a poor prognosis in multivariate analysis. High-risk WPOI was also of independent prognostic significance.[70]

Nomograms have been developed for various cancers including head and neck which can estimate survival based on specific tumor and host characteristics. In a review of 1617 patients with oral cavity cancers treated at MSKCC, nomograms were generated for predicting OS, cancer-specific mortality probability (CSMP), and locoregional recurrence-free probability (LRRFP). The nomograms were internally validated with a concordance index for OS of 67%, CSMP of 66%, and LRRFP of 60%.[71]

The other issue with the factors discussed above is the standardization of pathologic reporting across institutes and a minimum data set that needs to be reported. This also underscores the importance of specialty care to enhance patient care. This brings into focus the utility of artificial intelligence and machine learning to identify not only pathologic parameters but also molecular markers in this group of patients.

  Conclusion Top

Even though single modality management is preferred for early oral cancers, treatment intensification may be necessary for almost a fourth of patients with clinical, early-stage disease in the presence of various adverse risk features. Some of them include close margins, extensive PNI, LVI, and poor differentiation. Both retrospective and prospective studies have provided conflicting results regarding the use of adjuvant treatment. Often, treatment decisions in this intermediate group are taken based on treating oncologists' discretion and institutional practice. More randomized trials, risk assessment models, and nomograms need to be developed to maximize outcomes and reduce treatment-related morbidities.

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