Neoadjuvant chemotherapy for advanced oral cavity cancer
Authors: Dan Yaniv, Tanguy Y. Seiwert, Danielle N. Margalit, Michelle D. Williams, Carly E. A. Barbon, Rene D. Largo, Jon A. Smith, Neil D. Gross
Journal: CA A Cancer Journal for Clinicians (2024)

A Caucasian male aged 51 years presented with tongue pain, odynophagia, right otalgia, and weight loss. Physical examination showed a tender, ulcerative mass of the posterior lateral tongue and crossing the midline. A biopsy confirmed invasive oral tongue squamous cell carcinoma (SCC). Computed tomography (CT) imaging revealed a deeply invasive tumor involving the right oral tongue, extending across the midline and almost to the contralateral tongue border (Figure 1). The tumor measured 3.5 × 4.3 × 4.3 cm with an infiltrative pattern and poorly defined borders. Bilateral pathologic upper cervical lymph nodes were observed. The tumor was classified as clinical stage IVA (T4aN2cM0). Baseline imaging. Representative (A) axial and (B) coronal computed tomography images of a deeply invasive, right oral tongue squamous cell carcinoma (classified as T4a) crossing the midline. Primary surgical resection would require subtotal glossectomy. The patient's past medical history was negative for exposure to risk factors for head and neck cancer, including prior smoking, alcohol, or illicit drug use. The patient works as a SWAT team commander, an occupation in which loss of speech would result in permanent disability. After a multidisciplinary discussion, the decision was made to treat the patient with neoadjuvant chemotherapy followed by surgery, including free-tissue transfer reconstruction and adjuvant radiation therapy (RT). The patient was given three cycles of combined docetaxel, cisplatin, and 5-fluorouracil (TPF). The patient tolerated neoadjuvant chemotherapy very well and noted improvement in pain and eating with treatment. He gained >15 pounds and was able to resume a normal diet from a previously self-restricted diet secondary to pain. Restaging CT imaging showed that the primary tumor had decreased in size to 2.9 × 2.1 × 3.6 cm, corresponding to a 66% decrease in volume (Figure 2). Importantly, the primary tumor had regressed closer to the midline. Enlarged lymph nodes remained present in the neck bilaterally but had similarly decreased in size. The patient was evaluated preoperatively by a speech pathologist, and a modified barium swallow study revealed all phases of swallow within normal limits. The examination was without aspiration/laryngeal penetration or pharyngeal retention, and the motor speech system was functional. Postneoadjuvant imaging. Representative (A, B) axial and (C, D) coronal computed tomography (CT) images (A, C) before and (B, D) after neoadjuvant treatment with three cycles of docetaxel, cisplatin, and 5-fluorouracil. The patient then underwent response-adapted oncologic surgery, including right partial (<50%) glossectomy to encompass all clinical and radiographic residual disease with frozen-section analysis of all margins (taken from the specimen). Bilateral, selective neck dissection was performed as well as tracheostomy, percutaneous gastrostomy tube placement, and free-tissue transfer reconstruction with a neurotized lateral forearm fasciocutaneous flap (Figure 3). The patient was decannulated after 6 days and was discharged 8 days after surgery. Postneoadjuvant photograph. Clinical photograph showing right tongue tumor after neoadjuvant treatment and before surgery. The final pathology demonstrated 0.9-cm residual viable tumor in the tongue specimen with a depth of invasion of 6 mm (Figure 4). Perineural invasion was identified. All specimen margins were confirmed as negative. Within the bilateral neck dissection, a 0.4-cm focus of viable tumor was identified in one of 77 lymph nodes. Extranodal extension was not identified, although location relative to the capsule of the node can be difficult to definitely ascertain after neoadjuvant treatment (Figure 5). The patient was classified under the American Joint Committee on Cancer (AJCC) AJCC Cancer Staging Manual, eighth edition, with pathologic (yp) stage III disease (ypT2N1M0). Based on these findings, he received adjuvant RT (60 grays in 30 fractions). Postneoadjuvant microscopic images of primary tumor. Microscopic images of the resected primary tumor after neoadjuvant treatment. (A) At low-power magnification, the primary tumor in the tongue shows cords of tumor with associated desmoplastic response. The surrounding background tissue shows dense hyalinization/fibrosis consistent with treated tumor bed. (B) At high-power magnification, dense hyalinization, fibrosis, and chronic inflammation are observed adjacent to viable tumor (lower left). Multinucleated giant cells (right) are commonly seen after neoadjuvant treatment. Postneoadjuvant microscopic image of cervical lymph node. Microscopic low-power image of a resected cervical lymph node with marked treatment effect and effacement of nodal architecture after neoadjuvant treatment. Fibrosis replaces tumor, with focal, viable tumor present toward the periphery of the node (top and bottom of image). A modified barium swallow test was done 2 weeks after surgery (Figure 6) and showed mild-to-moderate oral phase dysfunction and functional pharyngeal swallow (grade 0 according to Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] version 2). Repeat speech pathology evaluation 2 months after adjuvant RT indicated that his speech intelligibility was 100% with minimal postoperative dysarthria. His voice was within functional limits with mild dysphonia, mild roughness, and mild strain. The patient was eating a regular diet by mouth, and his percutaneous gastrostomy tube was removed. Early postsurgical photograph. Clinical photograph showing ability of patient to achieve right tongue protrusion after neoadjuvant treatment and surgery. Response-adapted oncologic surgery allowed for complete extirpation of residual oral tongue squamous cell carcinoma and preservation of tongue parenchyma after neoadjuvant chemotherapy. A lateral arm fasciocutaneous flap was used for immediate reconstruction. The patient was able to resume working full-time. He has mild dysarthria and has adapted his diet. He remains disease-free >3 years after surgery. National Comprehensive Cancer Network (NCCN) guidelines for the management of oral cavity SCC indicate that surgery is the preferred initial treatment, including for advanced (T3, T4a) primary oral tongue cancers.1 This is based on data showing improved survival with surgery compared with concurrent chemoradiotherapy as definitive treatment in oral tongue SCC.2, 3 However, primary surgery can be functionally devastating in some patients, even with optimal reconstruction, particularly for cancers that require >50% resection of the tongue. As such, for selected patients who decline or are not candidates for resection, nonsurgical options are suggested alternative treatment options, including definitive RT or concurrent chemoradiation. The recommendation for primary surgery is based on historical precedence and NCCN guidelines. When surgery is performed for oral tongue SCC, there are technical factors that can impact prognosis. Margin status is one of the most important variables associated with survival for oral tongue SCC.4, 5 Traditionally, a 5-mm margin on final pathology is recommended for oral tongue SCC. To achieve this, a 10-mm margin is typically required in surgery to allow for expected shrinkage of the specimen in formalin. More recently, Liao et al. found that 7 mm was the ideal intraoperative resection margin for ensuring an adequate oncologic resection without sacrificing normal tongue tissue, because a planned intraoperative margin smaller than 7 mm was found to decrease local relapse-free survival on multivariate analysis.6 In a retrospective study that included 381 patients with oral cavity SCC who were reviewed by dedicated head and neck pathologists, it was found that local recurrence-free survival was significantly affected only with pathologic surgical margins ≤2.2 mm, considerably less than the traditional 5 mm on final pathology.7 Regardless, it is incumbent upon the surgeon to remove the cancer completely while preserving as much normal tissue as possible, and close collaboration with pathology during surgery is critical for success. Appropriate management of lymph nodes is also critical in the treatment of oral tongue SCC. This was demonstrated in a retrospective analysis of 4341 patients who had pathologic node-negative (pN0) oral cavity SCC in which the number of nodes dissected was a significant predictor of overall survival (OS; ≥22 nodes: hazard ratio [HR], 0.854; p = .031). The authors also calculated that, with each additional lymph node removed, survival was increased (HR, 0.995; p = .022).8 A similar analysis of the National Cancer Database demonstrated that patients who presented with clinically node-negative (cN0) oral cavity SCC who had <16 lymph nodes removed had significantly decreased survival.9 More recently, a lymph node density (the number of positive lymph nodes divided by the total number of lymph nodes dissected) cutoff >0.06 was correlated with worse OS.10 However, lymph node density has yet to be incorporated into NCCN guidelines. From a surgical standpoint, the role of neoadjuvant systemic therapy is less well defined. To date, there are no standardized surgical guidelines for patients who are treated with neoadjuvant systemic therapy. In a retrospective analysis comparing perioperative morbidity between patients with oral cavity SCC receiving chemotherapy before surgery (n = 147) or not (n = 687), there was no difference with regard to wound complications (p = .47), return to the operating room (p = .31), or readmission rates (p = .49). The neoadjuvant chemotherapy group received more blood transfusions (p < .001) but was found to have a lower risk of overall complications on multivariate analysis (odds ratio, 0.50; 95% confidence interval, 0.30–0.83).11 The impact of induction or neoadjuvant chemotherapy on outcomes for oral cavity SCC has been a matter of debate, with conflicting results for survival versus functional outcomes/organ preservation. Two published phase 3 randomized trials evaluated the role of neoadjuvant chemotherapy followed by surgery with or without postoperative RT (PORT) in patients with advanced oral cavity SCC. Those studies focused on investigating a potential survival benefit and were not focused on organ preservation. In a first study, 195 patients were randomly assigned to either three cycles of neoadjuvant chemotherapy with cisplatin plus fluorouracil followed by surgery or up-front surgery. Patients deemed at high risk on final pathology (positive margins, three or more positive nodes, extranodal extension, or invasion of the soft tissue of the neck or cheek) received PORT. There were no differences in 5-year OS, locoregional relapse, or distant relapse.12 Those who received neoadjuvant therapy were less likely to require mandible resection compared with those who underwent up-front surgery (31% vs. 52%, respectively). At a median follow-up of 11.5 years, there was no difference in the incidence of locoregional relapse (p = .63), distant metastasis development (p = .15), or OS (p = .34). However, patients who had a pathologic complete response had a higher probability of survival than those without (10-year OS: 76.2% vs. 41.3%; p = .0004). Although late toxicities were similar between arms, those who received neoadjuvant therapy reported lower rates of fibrosis compared with those who underwent up-front surgery (22% vs. 40%, respectively) and moderate dysphagia (5% vs. 14%, respectively).13 In a second study, Zhong et al. randomly assigned 256 patients to receive either two cycles of TPF neoadjuvant chemotherapy or up-front surgery. All patients received PORT. The median follow-up was 30 months, and no differences in OS, disease-free survival, or locoregional recurrence were observed between the groups.14 Again, patients who had a favorable pathologic response or a clinical response after neoadjuvant chemotherapy had better clinical outcomes (locoregional control, distant control, and OS). Hence a survival benefit has not been established with neoadjuvant therapy. However, a meta-analysis of these two phase 3 studies suggested that a subgroup of patients with advanced nodal (cN2) disease may benefit.15 By contrast, a retrospective study of neoadjuvant TPF in 167 patients who had oral cavity SCC found that response to neoadjuvant chemotherapy was negatively associated with N classification (p < .001) and overall clinical stage (p = .004). Patients who had bulky nodes or nodes with obvious tumor necrosis had lower response rates and progressed more frequently with neoadjuvant TPF chemotherapy.16 Two newer, large nonrandomized case series confirmed the feasibility of neoadjuvant treatment to achieve high rates of organ preservation. In one review of 120 patients who received two cycles of TPF induction chemotherapy,17 76 patients (63%) achieved a response (measured as tumor shrinkage ≥30%), including 13 (11%) who had a complete response (resolution of tumor on imaging). Among the 44 patients without a response, organ preservation was generally not feasible, and fewer of these patients underwent surgery compared with those who had a response (70% vs. 79%, respectively). Patients who had at least a partial response had improved 5-year OS (60%) and disease-specific survival (79%) compared with those who did not respond (stable and progressive disease) (34% and 46%, respectively). In a second case series that included 140 patients with oral cavity SCC, all patients were treated with definitive chemoradiation to achieve organ preservation. Induction chemotherapy (platinum/taxane-based) was tolerable/feasible and showed a nonsignificant trend toward improved progression free survival (HR, 0.65; p = .11) and OS (HR, 0.74; p = .34).18 The most recent randomized study, a phase 2 trial by Chaukar et al., specifically focused on organ preservation.19 Sixty-eight patients with oral cavity SCC requiring a segmental mandibulectomy were randomly assigned to either up-front surgery or two cycles of neoadjuvant TPF before surgery plus postoperative therapy. Postoperative therapy in the control arm was provided as indicated by pathologic classification, whereas all patients in the neoadjuvant chemotherapy arm received PORT with concurrent weekly cisplatin regardless of their pathologic response. The study met its primary end point of mandibular preservation, with 47% of patients in the neoadjuvant chemotherapy arm defined as being able to avoid a segmental mandibulectomy without compromising recurrence. Induction was again found to be feasible, but the rate of grade 3 and 4 toxicity during neoadjuvant therapy was greater than 30%. OS has not been reported. Taken together, these data suggest that the potential benefit of induction/neoadjuvant chemotherapy is organ preservation rather than a significant impact on survival. However, response to neoadjuvant therapy consistently identifies patients who have favorable outcomes, suggesting that this approach may be useful for selecting patients for more aggressive therapy. In our case study, organ preservation was a key priority for the patient. The possible benefit of neoadjuvant systemic therapy should be weighed on a case-by-case basis against the possible risks, including adverse effects, such as neutropenia and the delay of surgery. For people undergoing surgery for tongue cancer, the reconstructive options for a hemiglossectomy defect include secondary intention healing, primary closure, synthetic skin substitute, skin graft, regional pedicle flap, and free flap reconstruction. A thin, pliable free flap provides the best outcomes in hemiglossectomy defects because of decreased scaring and tethering of the tongue, resulting in better tongue mobility for articulation and swallowing.20, 21 A thin, pliable flap with innervation was planned in this patient given the defect characteristics. The patient's thinnest skin on examination was identified to be the lateral forearm region, overlying the lateral epicondyle. A lateral forearm flap was the preferred reconstructive option.22 This was selected over alternative options, including a distal forearm flap, such as the radial forearm flap and the ulnar artery perforator flap, which both sacrifice a major vascular inflow to the hand and have a higher rate of delayed wound healing, including skin graft loss and tendon exposure.23, 24 Alternative donor sites from the calf (medial sural artery perforator)25 and the groin (superficial iliac circumflex artery perforator)26 were not selected because of the expected increased subcutaneous fat in these regions. A submental island flap was not favored because of the bilateral neck dissection.27 The harvest of a lateral forearm, ulnar artery, or medial sural artery perforator flap allows the inclusion of a cutaneous nerve with the flap. Sensate flaps are preferred for the management of oral and oropharyngeal cancer because of increased patient satisfaction and improved two-point discrimination.21, 28-31 However, the potential utility of sensate flaps is controversial because of the incongruity of study methods.32, 33 Pathologic evaluation of neoadjuvant specimens requires thorough assessment to appropriately document tumor status and margins. Margin assessment at the time of intraoperative assessment is challenging secondary to extensive fibrosis in the tumor bed with ill-defined margins post neoadjuvant therapy. Residual viable tumor may be localized or multifocal within the tumor bed with various sized tumor nests. Gross palpation is less reliable, leading to the importance of additional histologic sections for microscopic review. Thorough sectioning allows for documentation of the presence and extent of viable tumor along with assessment of critical biologic factors, including perineural invasion. Similar attention is required for lymph nodes to document the extent of remaining viable tumor. The lymph node capsular edge and the assessment of extranodal extension also are less defined because the nodal tissue is replaced with fibrosis. Pathologic findings postneoadjuvant therapy remain descriptive because there is yet no standardized grading system of pathologic response in the head and neck. Reporting criteria for AJCC staging uses the prefix y when neoadjuvant therapy was given regardless of the presence or absences of tumor response. Pathologic (p) tumor (T) and nodal (N) classifications after neoadjuvant therapy are evaluated based on the viable tumor identified using the same criteria as a nontreated tumor. So, ypT classification is based on the overall area within the tumor bed that shows residual viable tumor foci. Tumor response may be estimated and reported as the percentage of viable tumor determined by the size of viable tumor nests divided by the tumor bed area, as designated by fibrosis/scar, and multiplied by 100. Multiple viable foci within the tumor bed after neoadjuvant therapy should not be coded as multifocal (m) disease under the AJCC staging system. The benefit of PORT is to reduce the risk of a local or regional (i.e., lymph node) recurrence after surgery. Local-regional recurrences are more common than distant metastases for most mucosal head and neck cancers, including that of the presented patient, who has an advanced oral tongue cancer. Cure rates after local-regional recurrences are low, and such recurrences can be highly symptomatic and associated with a reduced quality of life.34 Therefore, careful application of PORT is important to avoid morbid, life-threatening recurrences. The standard indications for PORT are based on pathologic risk factors, in the absence of neoadjuvant therapy, including pathologic T3 or T4 tumors, lymph node >3 cm, multiple positive lymph nodes, lymphovascular invasion, and perineural invasion (refer to NCCN guidelines). For particularly high-risk patients who have positive margins or extranodal extension, the addition of postoperative chemotherapy to RT is associated with improved local-regional control and survival.35-37 Because the use of neoadjuvant therapy before surgery is less common than upfront surgery, there are less data for guidance on who should receive adjuvant RT, particularly after a complete pathologic response. Consequently, it can be challenging for a clinician to decide whether a patient with locally advanced cancer should receive PORT if they had a major pathologic response and no longer have the standard pathologic indications listed above. In this case, if the patient were to proceed straight to surgery without neoadjuvant therapy, then they would be counseled on surgery followed by PORT based on the anticipated pT4 classification. The RT would be delivered to the initial extent of disease and the at-risk regional lymph nodes. However, if the patient were to receive neoadjuvant systemic therapy, can RT be safely omitted if there is a complete pathologic response such that they no longer have viable tumor in the specimen and lack traditional indications for PORT? There is guidance regarding when induction chemotherapy is given before definitive chemoradiation, as done in seminal phase 3 studies of patients who had tumors deemed unresectable or were candidates for organ preservation.38, 39 In this context, RT is delivered to the initial pretreatment disease extent, even if there is a complete clinical response to induction chemotherapy.40 The rationale for this practice is that tumors do not shrink concentrically, and microscopic disease may exist even when gross disease is no longer visible on examination or imaging. There are published clinical trials in nonoral cavity cancers, such as for nasopharyngeal cancer41 or oropharynx cancer,42 that reduce the dose and extent of RT based on the response to induction chemotherapy, but this is not yet standard practice. The three neoadjuvant studies discussed above from India,1 China,43 and Italy44 provide examples of how clinicians may approach the application of PORT when neoadjuvant chemotherapy precedes surgery. Two of the trials took a conservative approach, requiring that all patients in the neoadjuvant arms receive RT to the initial extent of disease.19, 43 Chaukar et al.,19 in a trial aimed at reducing the extent of surgery, maintained the PORT to avoid increasing the risk of local-regional failure if they were to reduce both surgery and RT at the same time. For Zhong et al.,43 the primary end point was OS. By ensuring all patients received RT to initial sites of disease, they avoided the potentially detrimental effect of local-regional failures on the primary end point. Only the study by Licitra et al.44 omitted RT for patients who did not have prespecified pathologic risk factors, and there was no obvious detriment to local-regional control. A large phase 3 trial, KEYNOTE-689 (ClinicalTrials.gov identifier NCT03765918), is accruing at the time of this writing. It randomly assigns patients who have stage III–IV head and neck SCC to receive either standard surgery with postoperative therapy based on pathology or neoadjuvant and adjuvant pembrolizumab. In that study, all patients who receive neoadjuvant therapy receive postoperative therapy to the initial disease extent, regardless of the treatment response. In summary, after neoadjuvant therapy, PORT is given for standard pathologic indications after surgery and for advanced tumors on initial clinical staging. The challenge is when to give PORT if there is substantial downstaging such that the final pathologic stage is discordant from the initial pretreatment clinical stage. Reducing postoperative treatment is appealing because it is associated with substantial acute toxicity and late effects. Reducing postoperative treatment must be done in a systematic fashion because of the established role of PORT in improving oncologic outcomes of patients with head and neck cancers. For this patient with a very locally advanced tumor, we would anticipate recommending PORT regardless of the pathologic response to neoadjuvant chemotherapy based on the initial extent of disease and the historical precedent described previously.45-47 Ablative surgery of the oral tongue results in alterations to speech intelligibility, articulatory precision, and swallow function that ultimately affect quality of life and performance status. The tongue interacts precisely with nearby structures, such as the teeth, alveoli, and the palate, to perform the motions of articulation.48 Mobility of the oral tongue is critical for speech, mastication, oral health, and swallow function. Decreased lingual range of motion (ROM) heavily affects the oral phase of swallowing, whereby patients have trouble with chewing, bolus formation, and transit of the bolus from the anterior tongue to the posterior tongue to trigger the swallow. This often results in leftover residue on the lingual and/or palatal surfaces. Furthermore, patients may report impaired articulation or phoneme distortions (speech precision).49, 50 Findings of a systematic review after ablation and free flap reconstruction of the tongue revealed that the extent of speech impairment relies on multiple factors, such as tumor size, preservation of tongue tip, method of reconstruction, flap sensation, and adjuvant therapy. Factors that affect postoperative swallowing outcomes include adjuvant therapy and method of reconstruction.51 Additional determinants of speech and swallow function after glossectomy include tumor size and depth (e.g., cross-midline), tumor location (e.g., anterior vs. posterior), extent of resection of adjacent subunits (e.g., floor of mouth, tonsillar pillar), and type of reconstruction (e.g., primary closure, skin graft, free flap, or healing by secondary intention). Poor functional outcomes are associated with reduced postoperative lingual ROM. Recent data identified four clinically distinct glossectomy defects using validated measures of speech intelligibility, quality of life, and functional status. A comparison of functional outcomes by glossectomy defect in 101 patients (37 underwent subtotal hemiglossectomy, 33 underwent hemiglossectomy, 16 underwent extended hemiglossectomy, and 15 underwent oral glossectomy) revealed differences in intelligibility.52 For example, sentence intelligibility differed significantly between the four groups, with a decrease in intelligibility as the defect increased (subtotal hemiglossectomy, 92% intelligibility; hemiglossectomy, 90% intelligibility; extended hemiglossectomy, 83% intelligibility; and oral glossectomy, 70% intelligibility). Clinically, the concept of speech intelligibility differs from articulatory precision. Patients may present as intelligible and yet appreciate the deviations in precise articulation of various speech sounds. In a study comparing both speech (including evaluations of speech rate and overall quality and intelligibility) and swallowing using nonvalidated methods (mean bolus volume ingested, duration of swallow, and mean volume swallowed per second), speech quality was better in patients who underwent primary closure. However, swallowing outcomes were better for those who underwent free flap reconstruction. These results support restoration of volume in the oral cavity, thus improving tongue-to-palate contact, which facilitates oral and pharyngeal clearance. However, overly bulky flaps may limit lingual mobility and ROM, thus negatively affecting speech intelligibility and articulation.53 For example, the inability to approximate the tongue to the hard palate yields diffuse oral cavity residue particularly with solid foods. This is a result of impaired lingual sweeping and/or lack of tongue-to-palate contact that requires a variety of modifications or compensations (e.g., the use of a finger to clear the oral sulci because of limited ROM of the reconstructed tongue, head tilts to facilitate passive movement of a bolus). Functional ROM is critical to achieve optimal speech intelligibility and to advance diet complexity and is related to quality of life. These considerations are relevant to the patient presented because primary closure is typically not feasible in patients who have larger defects. With regard to swallowing function, patients who have larger defects present with significantly worse function on objective swallow evaluations (videofluoroscopy) compared with patients who have smaller defects.21, 54 Huang et al. found that tongue resection >50% was a strong predictor of penetration and aspiration.55 In a cross-sectional study assessing swallowing function in patients with oral tongue SCC who underwent surgery with or without reconstruction, 106 patients were evaluated with videofluoroscopy. The results revealed that the incremental volume of the glossectomy defect was associated with worse outcomes across all videofluoroscopy parameters. On multivariate analysis, this remained as the only independent predictor for oral videofluoroscopy parameters as opposed to method of reconstruction, T stage, and radiotherapy.56 The following testimony was written by our patient, detailing his experience with oral cavity cancer: In early 2020, I began to experience pain in my right ear. Initially, not much thought was given to it as my profession required that I spend much of my time in varying environments, and I believed I simply had an ear infection. With a visit to my health care provider, I learned that the pain was the result of an SCC tumor that originated on my tongue and had developed into a stage IV mass. I met with local oncologists, who informed me that my only option was complete tongue removal. As I continued to search for a plan of care locally, I seemed unable to find a partnership that possessed the same level of commitment for healing that I personally held. Their emphasis was focused solely on cure and not quality of life. That changed when I arrived for my initial visit at MD Anderson with Dr. Neil Gross. As the inquiry of my background began, I quickly emphasized that I was a Law Enforcement Instructor and that speaking, both publicly and privately, was at the center of my daily actions. Dr. Gross began to develop a nontraditional plan through using chemotherapy first to shrink the tumor and surgery to quickly follow. Finally, radiation would be used to cleanse the area. The plan was to save my tongue. I immediately knew I had located someone willing to be equally yoked in my healing. The commitment I had was built from my Christian faith and attributes taught to me by many industry professionals. First, my faith: My faith was and is the cornerstone that allowed me to maneuver through the challenges that cancer treatment posed. My Christian beliefs provided a mental peace and gave endurance when the difficult days would arrive. Second, my family. I am unable to describe the immeasurable devotion my wife had to being my caregiver. She spent countless hours and days keeping count of the plans for care and making sure I was following them. Last, the attributes learned through the years as a SWAT officer: The time spent being taught to endure hardships to accomplish goals and removing quit as an option. I learned to keep my world small; some days, I would work to make it to noon. Once there, I told myself to make it to the evening. Cancer treatment is too much when you consider it in its totality. You have to view it as a series of small goals and work to achieve them. This journey took 50% of my tongue and 77 lymph nodes, but it gave me much more. My tongue was rebuilt by harvesting from my arm. Today, I am 3 years with no evidence of disease and am able to speak. Looking back, strangely, I am thankful for having this experience. It forced me in a new direction. The mental and physical battles make you stronger if you let them. I am a better person today than before cancer. You have to see the benefits in things, even when they bring a short-term unpleasantry. Every profession has its particular phrases. I constantly heard the phrase, "your new normal." Too many take that as a deficit invitation. I learned to view it as possibility. My reply became, "my new normal is discipline and focus." Once home, I began the process of rebuilding myself physically. Learning to complete old tasks in different manners, rebuilding my mobility, and regaining the strength and weight lost to treatment. Along the way, I have learned to not be so rigid in my thinking. I learned quickly that my old routines were not as beneficial as before, and I had to adopt new routines to push myself forward. Today I have returned to my responsibilities and position at work. I instruct various courses of disciplines in our craft. Most importantly, I now teach a class at my church. I found the partnership commitment to my healing at MD Anderson. There are far too many to name, but they are all equally important. To say thank you to them all is so insufficient, but I will not forget their commitment to making cancer a thing of the past. The prognosis for advanced, resectable oral cavity cancer remains grim, with only one half of patients achieving disease-free status 5 years postsurgery. Despite efforts to enhance outcomes through intensified adjuvant treatments and preoperative chemotherapy, there has been little improvement in survival.14, 18, 57 Immunotherapy using immune checkpoint inhibitors has demonstrated efficacy in recurrent or metastatic head and neck mucosal SCC.58, 59 These promising results have prompted investigations into the potential impact of immunotherapy in earlier stages of the disease, including in the neoadjuvant setting. Pathologic responses have been observed after neoadjuvant immunotherapy alone in oral cavity SCC, and a randomized phase 3 trial is underway testing this approach.60, 61 There are also now smaller trials investigating neoadjuvant immunotherapy and chemotherapy in oral cavity SCC. This approach is particularly encouraging given the strength of the data in nonsmall lung cancer and warrants randomized trials. Tanguy Y. Seiwert reports personal/consulting fees from AstraZeneca, EISAI INC., Inate Pharma Inc., iTeos, Merck, Regeneron Pharmaceuticals, Sanofi, and Vir; and service on a Data and Safety Monitoring Board at BioNTech outside the submitted work. Michelle D. Williams reports personal/consulting fees from Bayer Healthcare and support for other professional activities from Springer outside the submitted work. Neil D. Gross reports grants/contracts and personal/consulting fees from Regeneron Pharmaceuticals Inc.; personal/consulting fees from DragonFly Therapeutics Inc., Intuitive Surgical Inc., Merck, Replimune, and Sanofi/Genzyme US Companies; and support for other professional activities from PDS Biotechnology Corporation outside the submitted work. The remaining authors disclosed no conflicts of interest.