Enhanced Recovery After Surgery and Perioperative Laryngectomy Outcomes.

OBJECTIVE: Patients undergoing laryngectomy are particularly vulnerable to postoperative complications secondary to social and nutritional barriers, substance abuse, and prior cancer treatment. Enhanced Recovery After Surgery (ERAS) programs may mitigate this vulnerability and improve postoperative complications and oncologic outcomes. The objective of this study is to evaluate the postoperative complication rate and oncologic outcomes of patients undergoing laryngectomy before and after ERAS program implementation. METHODS: A historic cohort of 50 patients who underwent laryngectomy at the Levine Cancer Institute, Charlotte, North Carolina from 2014 to 2019 (pre-ERAS) was compared to 33 patients who underwent laryngectomy after ERAS implementation from 2019 to 2020. The primary outcomes included length of stay (LOS), Clavien-Dindo postoperative complications through 30 days following discharge, overall survival (OS), and recurrence-free survival between pre-ERAS and ERAS groups. RESULTS: Demographic characteristics between the two groups were similar. ERAS pathway implementation led to core care element consistency and improvement in the clinical perioperative course, including preoperative nutritional intervention (p = 0.009), postoperative ventilator independence (p = 0.0004), and refractory nausea/emesis (p = 0.18). Severe (≥ grade 3) complications (p = 0.49) and LOS (p = 0.68) were similar between groups. No significant difference in Cox proportional modeling of OS (p = 0.60) or recurrence-free survival (p = 0.17) was noted. CONCLUSIONS: ERAS did not improve LOS, major postoperative complications, or oncologic outcomes in this cohort of patients who underwent laryngectomy. However, ERAS positively influenced secondary endpoints within the laryngectomy perioperative course, conferring qualitative health care benefits. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2262-2268, 2024.

Radiation therapy for cT1-2 carcinoma of the palatine tonsil diagnosed via a simple tonsillectomy: Dosimetry and patterns of care in the IMRT era.

OBJECTIVE: Small carcinomas of the palatine tonsil are often diagnosed via simple tonsillectomy, a maneuver with non-therapeutic intent. Herein, practice patterns for this unique situation are evaluated. PATIENTS AND METHODS: A retrospective review was performed across 10 facilities to identify patients with cT1-2 squamous carcinomas of the tonsil diagnosed by simple tonsillectomy between 2010 and 2018. Patients who received curative-intent intensity modulated radiotherapy (IMRT) without additional surgery were included. Target volumes were reviewed, and cumulative incidences of local failure and severe late dysphagia were calculated. RESULTS: From 638 oropharyngeal patients, 91 were diagnosed via simple tonsillectomy. Definitive IMRT with no additional surgery to the primary site was utilized in 57, and three with gross residual disease were excluded, leaving 54 for analysis. Margins were negative in 13%, close (<5 mm) in 13%, microscopically positive in 61%, and not reported in 13%. Doses typically delivered to gross disease (68-70.2 Gy in 33-35 fx or 66 Gy/30 fx) were prescribed to the tonsil bed in 37 (69%). Sixteen patients (29%) received doses from 60 to 66 Gy (≤2 Gy/fx) and one received 50 Gy (2 Gy/fx). No local failures were observed. One late oropharyngeal soft tissue ulcer occurred, treated conservatively (grade 2). At five years, the cumulative incidence of severe late dysphagia was 17.4% (95% CI 6.1-28.8%). CONCLUSION: Small tonsil carcinomas diagnosed by simple tonsillectomy represent a niche subset with favorable oncologic outcomes. Regardless, radiation oncologists tend to deliver full-dose to the tonsil bed. The necessity of this routine could be questioned in the modern era.

Defining targets to improve care delivery for T4 larynx squamous cell carcinoma.

Objective: United States oncology trends consistently demonstrate that nearly half of T4a larynx carcinoma patients are treated with larynx preservation, despite national guidelines favoring laryngectomy. This study identifies clinical decision-making drivers and defines patient subsets that should become targets for care improvement. Methods: Retrospective analysis of patients with cT4 squamous cell carcinoma of the larynx from US National Cancer Database 2005-2016. Demographic data and survival rates between clinical pathways were compared. Survival was estimated by Kaplan-Meier method with statistical comparisons assessed by log-rank test. Results: Of 11,556 patients with cT4 disease, laryngectomy (TL) was the initial treatment for 4627 (40%) patients. Larynx preservation via chemoradiation (CRT) occurred for 4307 patients. TL and CRT patients had similar Charlson-Deyo comorbidity indices and insurance status. TL patients had higher total tumor size, lower N3 rates and were more often seen at academic institutions (p < .0001). N0 surgery patients with adjuvant treatment demonstrated superior median survival (MS) compared to CRT (surgery + radiation MS: 69 months, surgery + chemoradiation MS: 66, CRT MS: 37.7), p < .0001. MS for N1/N2 disease patients was 56.5 months for surgery + radiation and 35.5 months for surgery + CRT, superior to CRT, MS 30.8 months, p < .0001. Tri-modality N3 patients with up front surgery had similar MS compared to CRT (surgery + chemoradiation 21.3 months vs. CRT 16.1), p = .95. Conclusion: National quality improvement initiatives are needed to promote guideline adherence and improve survival in advanced larynx cancer. Targets for such initiatives should be patients with limited or no nodal disease burden, that meet clear T4a imaging criteria. Level of Evidence: Level IV, non-randomized controlled cohort.

Survivorship Care Plans Improve the Identification of Post-radiation Hypothyroidism After Head and Neck Cancer Treatment.

BACKGROUND/AIM: Survivorship care programs (SCPs) educate patients on post-treatment side-effects, which may lead to earlier identification and mitigation of their impact. This study assessed the impact of SCP on identification and management of post-treatment hypothyroidism in a head and neck cancer population and evaluated socio-demographic factors in the effectiveness of SCPs. PATIENTS AND METHODS: A retrospective analysis was performed of sociodemographic and clinical characteristics of patients with head and neck cancer treated with radiation therapy between January 2011 and January 2019 at a large community cancer institution. Development of hypothyroidism was defined as elevated thyroid-stimulating hormone (TSH) or initiation of supplementation post-treatment. Cumulative incidence of hypothyroidism was analyzed with Gray's method. RESULTS: Of 608 patients, 483 (79%) had post-treatment TSH surveillance. A total of 203 (42%) of those patients developed hypothyroidism; 53 (11%) patients completed SCPs. The median follow-up was 1.4 (interquartile range=0.7-2.6) years with a median time until diagnosis of hypothyroidism of 1.2 (interquartile range=0.7-2.1) years. The median time to diagnosis was 12.0 months with SCP versus 14.2 months without. Race and insurance status were not associated with differences in thyroid surveillance. Patients with laryngeal cancer were at greatest risk of developing hypothyroidism (hazard ratio=1.92, confidence interval=1.44-2.56; p<0.077). Cumulative incidence of post-treatment hypothyroidism was higher in patients managed with SCP, 65.4% at 4 years, compared to those without (49.0%). Receipt of SCP was independently associated with an increased incidence of hypothyroidism detection (hazard ratio=1.51, confidence interval=1.04-2.20; p=0.030). CONCLUSION: In our experience, SCP utilization was independently associated with a diagnosis of hypothyroidism. This study supports implementation of a survivorship program for identification and management of post-treatment sequelae.

Identifying an oligometastatic phenotype in HPV-associated oropharyngeal squamous cell cancer: Implications for clinical trial design.

OBJECTIVES: Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials. MATERIALS AND METHODS: From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis. RESULTS: We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2-4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007). CONCLUSION: Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population.

Rethinking the 10-pack-year rule for favorable human papillomavirus-associated oropharynx carcinoma: A multi-institution analysis.

BACKGROUND: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. METHODS: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). RESULTS: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. CONCLUSIONS: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Well-differentiated thyroid cancer with aerodigestive tract invasion: Long-term control and functional outcomes.

BACKGROUND: Well-differentiated thyroid cancer (WDTC) invading the aerodigestive tract is an uncommon entity associated with significant morbidity and reduced survival. METHODS: We reviewed the surgical treatment, oncologic control, and functional outcomes of 69 consecutive patients with WDTC invading the upper aerodigestive tract. RESULTS: Complete tumor excision with negative margins was achieved in 62% of patients. Tracheostomy dependence (27%) and permanent hypoparathyroidism (49%) were present or the result of surgery. Seventy-one percent of patients ate a regular diet, 59% had normal speech, and the majority (62%) reported normal activities of daily living. The local, regional, and distant recurrence was 1%, 14%, and 23%, respectively. The 5-year overall survival (OS) and disease-free survival (DFS) was 71% and 45%, respectively. CONCLUSION: Surgical resection and appropriate adjuvant treatment can achieve excellent locoregional control while preserving function and quality of life. Long-term survival is limited by the high incidence of distant metastasis.

Extent of pathologic extracapsular extension and outcomes in patients with nonoropharyngeal head and neck cancer treated with initial surgical resection.

BACKGROUND: Lymph node extracapsular extension (ECE) is a known adverse prognostic factor in head and neck cancer and is an indication for adjuvant chemoradiation (CRT). However, the extent of ECE may provide additional prognostic information in the setting of adjuvant CRT. METHODS: This study included 350 patients with oral cavity cancer (72.6%) or bulky/nonfunctional laryngeal cancer (27.4%) who underwent initial surgical resection. Extent of ECE was graded from 0 to 4 based on the scale established by Lewis and colleagues. Multivariable analyses (MVA) were adjusted for primary site, pathologic risk factors, and adjuvant therapy. RESULTS: In univariate failure-free survival (FFS) analysis, there was no significant difference in FFS for patients with lymph node-positive disease and no ECE (grade 0) versus patients with ECE grades 1 through 3. However, patients with ECE grade 4 had significantly worse FFS. In MVA for FFS, differences between ECE grades 0 through 3 and grade 4 did not remain significant. In MVA of overall survival, ECE grade 4 was significantly associated with higher risk of death compared with ECE grade 0 (hazard ratio, 0.46; P = .02) and ECE grades 1 through 3 (HR, 0.41; P = .01). CONCLUSIONS: Dichotomous evaluation of ECE is useful for determining appropriate adjuvant therapy but has limited additional prognostic value in the setting of adjuvant CRT. The detrimental effect of ECE grades 1 through 3 relative to no ECE is effectively mitigated with adjuvant CRT, but ECE grade 4 retains a poorer prognosis despite CRT with regard to overall survival. Patients with ECE grade 4 may be candidates for trials investigating novel methods of adjuvant therapy intensification.

Poly (ADP-ribose) polymerase inhibitors in cancer treatment.

Recent research on inhibitors of poly (ADP-ribose) polymerase (PARP) has demonstrated their potential for improving cancer therapy. They inhibit protein poly (ADP-ribosyl)ation and thus affect numerous molecular and cellular functions, including DNA repair and cell survival, that are critical for such physiological and patho-physiological states as carcinogenesis, inflammation, and resistance to cancer therapy. In this review, we describe the biological basis underlying the use of these agents in cancer therapy, providing data from preclinical studies that demonstrate the synergistic interaction of PARP inhibitors with radiation and chemotherapeutics. We also summarize initial clinical trials of PARP inhibitors for cancer treatment.

HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells.

BACKGROUND: The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance. METHODS: Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. RESULTS: All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib. CONCLUSION: Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.

Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear. EXPERIMENTAL DESIGN: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature. RESULTS: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control. CONCLUSION: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model.

BACKGROUND: We investigated the effects of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR), alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma (HNSCC). METHODS: The in vitro effects of vandetanib (ZACTIMA) were assessed in 2 HNSCC cell lines on cell growth, apoptosis, receptor and downstream signaling molecule expression, and phosphorylation levels. We assessed in vivo effects of vandetanib and/or paclitaxel by measuring tumor cell apoptosis, endothelial cell apoptosis, microvessel density, tumor size, and animal survival. RESULTS: In vitro, vandetanib inhibited the phosphorylation of EGFR and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC. CONCLUSION: Vandetanib has the potential to be a novel molecular targeted therapy for HNSCC.

Effective drug delivery, in vitro and in vivo, by carbon-based nanovectors noncovalently loaded with unmodified Paclitaxel.

Many new drugs have low aqueous solubility and high therapeutic efficacy. Paclitaxel (PTX) is a classic example of this type of compound. Here we show that extremely small (<40 nm) hydrophilic carbon clusters (HCCs) that are PEGylated (PEG-HCCs) are effective drug delivery vehicles when simply mixed with paclitaxel. This formulation of PTX sequestered in PEG-HCCs (PTX/PEG-HCCs) is stable for at least 20 weeks. The PTX/PEG-HCCs formulation was as effective as PTX in a clinical formulation in reducing tumor volumes in an orthotopic murine model of oral squamous cell carcinoma. Preliminary toxicity and biodistribution studies suggest that the PEG-HCCs are not acutely toxic and, like many other nanomaterials, are primarily accumulated in the liver and spleen. This work demonstrates that carbon nanomaterials are effective drug delivery vehicles in vivo when noncovalently loaded with an unmodified drug.

Endograft stenting in the adolescent population for traumatic aortic injuries.

Traumatic thoracic aortic transections are uncommon in the pediatric population. These injuries are currently treated by open operative repair via thoracotomies. We present 2 adolescent patients with traumatic thoracic aortic transections who were repaired by endovascular techniques. Both adolescents, aged 16 and 17 years, were in high-speed motor vehicle collisions and presented with multisystem trauma. Patient 1 had a transection of the descending aorta and was repaired with two 23-mm (diameter), 3-cm-long endograft cuffs at 48 hours after injury because of her multiple organ injuries. She was hospitalized for 40 days. Patient 2 had a thoracic aortic transection just distal to the aortic arch. He was repaired within 12 hours of injury with a 24-mm and two 22-mm AneuRx endograft cuffs. He was hospitalized for 8 days. Both patients have recovered without complications at 13 and 21 months, respectively. Endovascular stenting, especially in critically ill patients, allows for definitive treatment of the vascular injury without the need for bypass and reduces the recovery time that is associated with thoracotomies. Short-term recovery and follow-up are encouraging for endovascular stenting in the adolescent population; however, further long-term follow-up is required.

Pediatric blunt trauma resulting in major arterial injuries.

Ten children, aged 4 to 14 years, sustaining blunt arterial trauma from motor vehicle collisions (6), bicycle accidents (2), and falls (2) were identified over a 10-year period. The arteries injured included the common iliac (3), abdominal aorta (2), carotid (2), brachial (2), and the subclavian, renal, and femoral artery (1 each). One patient had three arterial injuries. Six patients had associated injuries including a pelvic and lumbar spine fracture, Horner's syndrome, liver laceration, skull fracture, open humerus fracture, small bowel serosal tear, and a brachial plexus injury. Definitive diagnosis was made using arteriography (6), computed tomography (CT) scan (2), and physical examination (2). The types of arterial injuries found included incomplete transection, complete transection with pseudo-aneurysm formation, traumatic arteriovenous (AV) fistulas, complete occlusion, and dissection. Repair was accomplished by hypogastric artery interposition or bypass grafting, synthetic grafting with polytetrafluoroethylene (PTFE), reverse saphenous vein grafting, or primary repair, depending on the circumstances. An AV fistula between the carotid artery and cavernous sinus was embolized. All grafts remained patent with exception of the aorto-renal bypass graft at follow-up ranging from 1 month to 3 years. The principles for repairing vascular injuries in children are slightly different than those in adults. Every effort should be made to use autogenous tissue such as the hypogastric artery or saphenous vein for repair if possible. If not, PTFE grafts can be used, although the long-term patency of these grafts in growing children is not known.