Breaking Ground in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Novel Therapies Beyond PD-L1 Immunotherapy.

The treatment for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (anti-PD1) with or without chemotherapy has led to an improvement in survival. Yet, despite this therapeutic advancement, only 15%-19% of patients remain alive at four years, highlighting the poor survival and unmet need for improved therapies for this patient population. Some of the key evolving novel therapeutics beyond anti-PD1 in R/M HNSCC have included therapeutic vaccine therapies, bispecific antibodies/fusion proteins and multitargeted kinase inhibitors, and antibody-drug conjugates (ADCs). Multiple concurrent investigations of novel therapeutics for patients with R/M HNSCC beyond anti-PD(L)1 inhibition are currently underway with some promising early results. Beyond immune checkpoint inhibition, novel immunotherapeutic strategies including therapeutic vaccines ranging from targeting human papillomavirus-specific epitopes to personalized neoantigen vaccines are ongoing with some early efficacy signals and large, randomized trials. Other novel weapons including bispecific antibodies, fusion proteins, and multitargeted kinase inhibitors leverage multiple concurrent targets and modulation of the tumor microenvironment to harness antitumor immunity and inhibition of protumorigenic signaling pathways with emerging promising results. Finally, as with other solid tumors, ADCs remain a promising therapeutic intervention either alone or in combination with immunotherapy for patients with R/M HNSCC. With early enthusiasm across novel therapies in R/M HNSCC, results of larger randomized trials in R/M HNSCC are eagerly awaited.

A Mixed-Method Approach to Explore Successful Recruitment and Treatment of Minority Patients on Therapeutic Cancer Clinical Trials at a Tertiary Referral Center Using Photo-Elicitation Interviews.

Introduction: Under-represented minority patients (URM) enroll in cancer clinical trials (CCT) at low rates. To gain insight into barriers and facilitators to CCT enrollment, we conducted a mixed method study of URM patients who were successfully treated on a therapeutic CCT from 2018-2021 at all institutional sites. Methods: A retrospective chart review of 270 minority patients was conducted to identify patient demographics and characteristics. All living URM patients were requested to participate in a survey and qualitative interview using a photo elicitation technique. Results: Most patients who participated in a CCT were patients with solid tumors, metastatic disease, and did not live in a rural area. Survey data showed that the two most significant drivers of CCT enrollment were potential of benefit to self and to others (altruism). Direct recommendation from a healthcare provider to participate in CCT was critical. URM patients enrolled on a CCT experience a significant burden of symptoms and financial distress. Key themes identified from the interviews that motivated patients to participate included chance for cure, staying positive, altruism and advancement of science, and having diverse representation in research. Patient-level facilitators to participation included social support, cost coverage, and limited treatment options. Sytematic facilitators identified included minimizing logistical barriers, decentralizing cancer clinical trials, increasing awareness via patient narratives, diversifying research staff, minimizing cost, and being clear on puropose and benefit of the trial. Conclusion: Success stories of minority recruitment can provide useful information to enhance minority accrual. Photo elicitation interviews provide rich narratives of patient experience.

Real-World Implementation of Best-Evidence Cancer Distress Management: Truly Comprehensive Cancer Care.

BACKGROUND: Cancer distress management is an evidence-based component of comprehensive cancer care. Group-delivered cognitive behavioral therapy for cancer distress (CBT-C) is the first distress treatment associated with replicated survival advantages in randomized clinical trials. Despite research supporting patient satisfaction, improved outcomes, and reduced costs, CBT-C has not been tested sufficiently within billable clinical settings, profoundly reducing patient access to best-evidence care. This study aimed to adapt and implement manualized CBT-C as a billable clinical service. PATIENTS AND METHODS: A stakeholder-engaged, mixed-methods, hybrid implementation study design was used, and the study was conducted in 3 phases: (1) stakeholder engagement and adaptation of CBT-C delivery, (2) patient and therapist user testing and adaptation of CBT-C content, and (3) implementation of practice-adapted CBT-C as a billable clinical service focused on evaluation of reach, acceptability, and feasibility across stakeholder perspectives. RESULTS: A total of 40 individuals and 7 interdisciplinary group stakeholders collectively identified 7 primary barriers (eg, number of sessions, workflow concerns, patient geographic distance from center) and 9 facilitators (eg, favorable financial model, emergence of oncology champions). CBT-C adaptations made before implementation included expanding eligibility criteria beyond breast cancer, reducing number of sessions to 5 (10 total hours), eliminating and adding content, and revising language and images. During implementation, 252 patients were eligible; 100 (40%) enrolled in CBT-C (99% covered by insurance). The primary reason for declining enrollment was geographic distance. Of enrollees, 60 (60%) consented to research participation (75% women; 92% white). All research participants completed at least 60% of content (6 of 10 hours), with 98% reporting they would recommend CBT-C to family and friends. CONCLUSIONS: CBT-C implementation as a billable clinical service was acceptable and feasible across cancer care stakeholder measures. Future research is needed to replicate acceptability and feasibility results in more diverse patient groups, test effectiveness in clinical settings, and reduce barriers to access via remote delivery platforms.

Capecitabine for Salvage Treatment of Patients With Heavily Pretreated Human Papillomavirus-Associated Oropharynx Cancer With Distant Metastases.

Background: Patients with metastatic human papillomavirus-associated oropharyngeal cancer (HPV-OPC) have a median overall survival exceeding 2 years and are often candidates for multiple lines of palliative therapy. With the approval of immunotherapy as first-line treatment, salvage therapeutic options are limited. We describe our experience using capecitabine as salvage therapy for patients with recurrent or metastatic (R/M) HPV-OPC. Methods: We performed a retrospective study of patients with R/M HPV-OPC with distant metastatic disease. Eligible patients were identified from a medical oncology clinical database. Demographic and clinical data were abstracted from the medical record. Survival probabilities were estimated with the Kaplan-Meier method. Results: 10 patients were identified. Sites of metastatic disease included lung, liver, mediastinal lymph nodes, bone, abdominal lymph nodes, and soft tissue. Most patients received capecitabine as fourth-line treatment. The median duration from start of capecitabine therapy until death was 10.5 months. Best treatment response was as follows: partial responses (PR) were seen in 4 of 10 (40%), stable disease (SD) in 3 of 10 (30%), and progressive disease (PD) in 2 of 10 (20%). The clinical benefit rate (CR + PR + SD) was 70%. Reasons for discontinuation included disease progression (n = 8) and side effects (n = 2). One patient notably had prolonged benefit from capecitabine and continued to be on treatment for 34 months total. Conclusions: Capecitabine is a potential salvage treatment for heavily pretreated patients with R/M HPV-OPC, with some patients experiencing prolonged response. Clinical or molecular predictors of response would be helpful to identify patients likely to benefit; a larger prospective study would be useful to confirm efficacy in this patient population.

A prospective, randomized trial of patient-reported outcome measures to drive management decisions in hematology and oncology.

Background: Clinicians have limited time during patient encounters which can result in patients' concerns not being addressed. This study's objective was to test whether an electronic patient-reported outcome quality of life tool (PROQOL) in which patients identify their primary concern during clinic visits improves cancer patient quality of life (QOL). Patients and methods: This single center non-blinded prospective clinical trial randomized patients (2:1) to PROQOL versus usual care (UC). Two patient cohorts were enrolled: those with hematologic malignancies (multiple myeloma [MM] or light chain amyloidosis [AL]) and solid tumors (head and neck [H/N] or gynecologic [GYN] malignancies). Primary endpoint was patient-reported QOL at 12 months measured by a single-item Linear Analog Self-Assessment. Value to patients and impact on clinician workflow was measured using a "was it worth it" survey. The study was powered to detect a 0.5 standard deviation difference between groups. Results: Overall 383 patients were enrolled, 171 with MM, 62 AL, 113 GYN, and 37 H/N between July 2016 and April 2018, with 12-month follow-up. There were 171 (44.6%) male patients and median age was 62 years (range 31-87). The most often selected concern was physical health (30.9%), and second was cancer diagnosis and treatment (29.1%). Mean QOL was 7.12 for PROQOL and 6.98 for UC (0-10 scale) at 12 months, with no between-group difference overall (p = 0.56) or within hematologic or solid tumor cohorts, respectively. Among patients, 74% thought the PROQOL tool was worthwhile, 86% would choose PROQOL again, and 81% would recommend it to others. Among clinicians, 95% responded that PROQOL was worthwhile and did not think that PROQOL negatively impacted their workflow. Conclusions: Although we did not demonstrate a QOL difference between PROQOL and UC groups; the PROQOL tool held considerable value in identifying patients' main concerns over time and was worthwhile for patients and clinicians.

Emerging Disparities in Prevention and Survival Outcomes for Patients with Head and Neck Cancer and Recommendations for Health Equity.

PURPOSE OF REVIEW: The aim of this review is to describe less known and emerging disparities found in the prevention and survival outcomes for patients with head and neck cancer (HNC) that are likely to play an increasingly important role in HNC outcomes and health inequities. RECENT FINDINGS: The following factors contribute to HNC incidence and outcomes: (1) the effect of rurality on prevention and treatment of HNC, (2) dietary behavior and nutritional factors influencing the development of and survival from HNC, and (3) barriers and benefits of telehealth for patients with HNC. Rurality, nutrition and diet, and telehealth usage and access are significant contributors to the existing health disparities associated with HNC. Population and culturally specific interventions are urgently needed as well as more research to further define the issues and develop appropriate population and individual level solutions.

Assessment of Discrimination, Bias, and Inclusion in a United States Hematology and Oncology Fellowship Program.

Importance: Medical trainees frequently experience discrimination. Understanding their experiences is essential to improving learning environments. Objective: To characterize trainee experiences of discrimination and inclusion to inform graduate medical education (GME) policies. Design, Setting, and Participants: This qualitative study used an anonymous telephone interview technique to gather data from hematology and oncology fellows. All current trainees and recent graduates were eligible. Interviews were conducted anonymously with interviewer and participant in separate locations and recorded and transcribed. Data were analyzed in an iterative process into major themes using a general inductive analysis approach. Demographic information was obtained via anonymous survey. Data collection and analysis were conducted from July 2018 to November 2019. Main Outcomes and Measures: Emergent themes illustrating bias and inclusion in a GME program. Results: Among 34 fellows and recent graduates who were approached for this study, 20 consented and 17 were interviewed. Of those interviewed, 10 were men, and the median (range) age was 32 (29-53) years. The racial and ethnic distribution included 6 Asian individuals, 2 Black individuals, 3 Hispanic individuals, 2 multiracial individuals, and 4 White individuals. All fellows reported having experienced and/or witnessed discriminatory behavior. The themes elucidated were (1) foreign fellows perceived as outsiders, (2) US citizens feeling alien at home, (3) gender role-typing, (4) perception of futility of reporting, (5) diversity and inclusion, and (6) coping strategies. The majority of reported biases were from patients. Only 1 trainee reported any incidents. Reasons for not reporting were difficulty characterizing discrimination and doubt action would occur. Participants reported that diversity of cotrainees, involvement in committees, and open discussions promoted inclusivity. Conclusions and Relevance: In this study, reports of discriminatory behavior toward trainees were common. The anonymous hotline methodology cultivated a safe environment for candid discussions. These findings suggest that GME programs should assess their learning climate regarding bias and inclusivity anonymously and develop processes to support trainees.

Human papillomavirus oropharynx carcinoma: Aggressive de-escalation of adjuvant therapy.

BACKGROUND: Aggressive dose de-escalated adjuvant radiation therapy (RT) in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC). METHODS: Patients with HPV(+)OPSCC on a phase II clinical trial of primary surgery and neck dissection followed by dose de-escalated RT (N = 79) were compared with a cohort of patients who received standard adjuvant therapy (N = 115). Local recurrence-free, regional recurrence-free, distant metastases-free survival, and progression-free survival (PFS) were assessed. RESULTS: Of 194 patients, 23 experienced progression at a median of 1.1 years following surgery (interquartile range [IQR] 0.7-2.0; range 0.3-5.4); 10 patients in the de-escalated cohort and 13 patients in the standard cohort. The 3-year PFS rate for the de-escalated cohort was 87%, and in the standard cohort was 90% (hazard ratio [HR] 1.18, 95% confidence interval (CI) [0.50-2.75]). CONCLUSION: Patients with HPV(+)OPSCC who undergo surgical resection and neck dissection and meet criteria for adjuvant therapy can undergo aggressive dose de-escalation of RT without increasing risk of progression locally, regionally or at distant sites.

Novel Strategies to Effectively De-escalate Curative-Intent Therapy for Patients With HPV-Associated Oropharyngeal Cancer: Current and Future Directions.

The treatment of patients with HPV-associated oropharyngeal cancer (HPV-OPC) is rapidly evolving and challenging the standard of care of definitive radiotherapy with concurrent cisplatin. There are numerous promising de-escalation strategies under investigation, including deintensified definitive chemoradiotherapy, transoral surgery followed by de-escalated adjuvant therapy, and induction chemotherapy followed by de-escalated locoregional therapy. Definitive radiotherapy alone or with cetuximab is not recommended for curative-intent treatment of patients with locally advanced HPV-OPC. The results of ongoing phase III studies are awaited to help answer key questions and address ongoing controversies to transform the treatment of patients with HPV-OPC. Strategies for de-escalation under investigation include the incorporation of immunotherapy and the use of novel biomarkers for patient selection for de-escalation.

Outcomes following TORS for HPV-positive oropharyngeal carcinoma: PEGs, tracheostomies, and beyond.

OBJECTIVES: To review swallowing, airway and speech outcomes following transoral robotic surgery (TORS) ±â€¯adjuvant therapy for human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV[+]OPSCC). METHODS: Patients underwent TORS ± standard adjuvant therapy from 5/1/2007-5/31/2015. Clinical data were recorded and descriptive analysis was performed. RESULTS: 267 patients met criteria. All patients underwent surgery at Mayo, however, only 41/81 and 71/119 patients received RT and CRT at a Mayo Clinic site. A PEG was placed in 77 patients (3 prior to any treatment, 74 reactively during adjuvant therapy), with 3 PEG dependent and 3 partially PEG reliant at last follow-up. Tracheostomy was performed in 30 (11%) patients; 28 were decannulated. Swallow evaluations were completed for 20/81 undergoing RT and 50/119 undergoing CRT at a median of 3.8 and 7.6 months post-treatment, respectively. An unrestricted oral diet was reported by 5% following RT and 12% following CRT on the Functional Oral Intake Scale. HN-PSS normalcy of diet scores indicated a diet beyond soft chewable foods for 27% following RT and 46% following CRT. No restriction of place, food, or companion was reported for the HN-PSS for public eating in 13% after RT and 33% after CRT. Aspiration of thin liquid was present in 17% and 28% following RT and CRT, respectively. HN-PSS understandability of speech was "always understandable" in 60% and 63%, following RT and CRT, respectively. Hoarseness was reported in 56% and 45% following RT and CRT respectively. CONCLUSION: Long-term PEG and tracheostomy dependence in this cohort is low. However, these outcomes under-represent the decrement in patient speech and swallowing following TORS ± standard adjuvant therapy for HPV(+)OPSCC.

Mechanisms of and therapeutic approaches for overcoming resistance to epidermal growth factor receptor (EGFR)-targeted therapy in squamous cell carcinoma of the head and neck (SCCHN).

The majority of squamous cell carcinoma of the head and neck (SCCHN) overexpress epidermal growth factor receptor (EGFR), which has been associated with poor treatment response and survival. However, only modest success has been achieved with the use of single agents that target EGFR, possibly due to primary and acquired resistance. This review will discuss key mechanisms of and therapeutic approaches to overcoming resistance to EGFR-targeted therapy in SCCHN. Recent preclinical and clinical investigations have demonstrated that other ErbB family receptors (eg, HER2 and HER3) and other horizontal resistance mechanisms, as well as activation of downstream signaling pathways, epigenetic events, and nuclear EGFR, are possible mediators of resistance to anti-EGFR therapeutics. Key downstream pathways that may be implicated in EGFR resistance include phosphatidylinositol-3-kinase/protein kinase B, vascular endothelial growth factor (VEGF), and mammalian target of rapamycin (mTOR). Multiple agents that target EGFR and other ErbB family members (ie, lapatinib, afatinib, and dacomitinib), as well as combination therapies that target EGFR and selected other pathways (eg, VEGF, mTOR, and c-Met) are being investigated clinically. In addition, several phase II and III trials continue to investigate strategies to enhance the efficacy of EGFR-targeted therapy in SCCHN.

Acinic cell carcinoma of the salivary gland with metastatic spread to the pancreas.

Metastatic disease to the pancreas is rare among solid tumors and has not been well described for salivary cancers. We report a patient who developed an isolated metastatic lesion in the pancreas from acinic cell carcinoma of the salivary gland, presenting as acute pancreatitis.

Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma.

OBJECTIVES: Standard treatment for patients with poor-risk, resected head and neck squamous cell carcinoma (HNSCC) is adjuvant radiation therapy combined with high-dose cisplatin. Many patients are treated with weekly cisplatin; it is not known whether weekly and high-dose cisplatin are equivalent. This study compares the outcomes of patients with locally-advanced HPV-negative HNSCC and HPV/p16-positive oropharynx HNSCC treated with adjuvant chemoradiation therapy with either high-dose or weekly cisplatin. MATERIALS AND METHODS: Retrospective review of patients with Stage III/IV HNSCC who had surgery followed by adjuvant chemoradiation therapy at Mayo Clinic, Rochester. HPV and/or p16 status was available for all oropharynx patients. RESULTS: 104 Patients (51 high-dose, 53 weekly) were analyzed. The 3-year overall survival was 84% and 75% for patients who received high dose and weekly cisplatin, respectively (p=0.30). The 3-year recurrence free survival was 71% and 74% in the high dose and weekly cisplatin group, respectively (p=0.95). Patients with HPV/p16-positive oropharynx cancer who received adjuvant chemoradiation therapy with high-dose and weekly cisplatin had three-year overall survival rates of 91% and 86% (p=0.56), and 3-year recurrence free survival of 84% and 82% (p=0.93). Extracapsular extension did not affect prognosis in either group. CONCLUSIONS: No significant survival difference was seen between patients with locally advanced HNSCC treated with adjuvant chemoradiation therapy with high-dose or weekly cisplatin, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity.

Risk of hemoptysis in patients with resected squamous cell and other high-risk lung cancers treated with adjuvant bevacizumab.

PURPOSE: Bevacizumab improves survival in lung adenocarcinomas. The potential anti-tumor benefit of bevacizumab in squamous cell lung cancers (SQCLCs) is unknown because bevacizumab is contraindicated in patients with advanced SQCLC due to an increased risk of hemoptysis. The risk of hemoptysis may be eliminated in patients with resected SQCLCs. We evaluated the safety of adjuvant bevacizumab in patients with resected SQCLCs and other lung cancers at high risk of hemoptysis. METHODS: As part of a prospective, phase II trial, patients with lung cancers at high risk of hemoptysis (defined by SQCLC histology, tumor near the central blood vessels, or history of hemoptysis) were treated with adjuvant bevacizumab following neo-adjuvant chemotherapy and complete surgical resection. Bevacizumab 15 mg/kg was given once every 3 weeks for up to 1 year. Patients were followed for safety and survival. RESULTS: Thirteen patients with high-risk features were treated: 7 patients had SQCLC, 3 had central tumors, and 3 had previous hemoptysis. No hemoptysis of any grade was seen following treatment with bevacizumab. Five of 13 patients experienced grade 1 bleeding (epistaxis, gum bleeding). Hypertension and lymphopenia were seen. CONCLUSIONS: In a cohort of patients with resected lung cancers at high risk of hemoptysis, including those with SQCLC, treatment with adjuvant bevacizumab did not result in hemoptysis of any grade.

Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers.

INTRODUCTION: Bevacizumab improves survival in patients with advanced non-small-cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable nonsquamous NSCLC. METHODS: Patients with resectable stage IB-IIIA nonsquamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single-agent effect. After this they received two cycles of bevacizumab with four cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety, and radiologic response. RESULTS: Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All three doses of neoadjuvant bevacizumab were delivered to 40 of 50 patients. Six patients (12%) discontinued because of bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable with historical data. No partial responses were observed to single-agent bevacizumab, but 18% of the patients developed new intratumoral cavitation, with a trend toward improved pathologic response (57% versus 21%; p = 0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% versus 49%; p = 0.01). No patients with KRAS-mutant NSCLC (0 of 10) had a pathologic response as compared with 11 of 31 with wild-type KRAS. CONCLUSION: Although preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS-mutant tumors.

Current treatment options for metastatic head and neck cancer.

Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged.

Hydration in cancer patients.

PURPOSE OF REVIEW: To provide an overview of issues central to hydration in an oncology population while highlighting recent advances and publications in the clinical and scientific literature. RECENT FINDINGS: Dehydration accounts for a significant number of unplanned visits to cancer clinics and emergency rooms. The decision to provide or withhold fluid in patients with terminal cancer is strongly influenced by subjective beliefs and the decision to use of hydration at the end of life should be individualized. Chronic dehydration may play a role in the pathogenesis of cancer. SUMMARY: Cancer patients are at high risk for dehydration from both the disease and the treatment. Treating physicians should have a low threshold for providing additional fluids to prevent dehydration. For patients at the end of life, hydration may be indicated in select patients.

Chemoradiation for unresectable stage III non-small cell lung cancer.

Patients with unresectable stage III nonsmall cell lung cancer (T4, N3, or bulky N2) live longer if they receive chemotherapy before or concurrent with thoracic irradiation. Randomized clinical trials have shown that concurrent chemoradiation is superior to sequential chemotherapy followed by radiation, with a 20% reduction in the risk of death compared with the sequential approach. However, concurrent chemoradiation is more toxic than the sequential approach, with an increased risk of radiation esophagitis, pneumonitis, and cytopenias, including febrile neutropenia. The phase III trials showing the superiority of the concurrent approach all used cisplatin-based chemotherapy and enrolled patients with a good performance status. For patients who are not eligible for cisplatin, or who have a poor performance status, weight loss, or poor lung function, a sequential approach may be used with full doses of chemotherapy followed by radiation. Another approach currently being studied in phase III trials is to use lower doses of chemotherapy concurrent with radiation followed by full-dose chemotherapy after radiation, so-called concurrent followed by consolidation therapy. Treatment should be planned by the radiation and medical oncologist with careful selection of approach based on the patient's fitness, comorbid medical illness, and size and location of the tumor. The goal of treatment is to maximize efficacy and minimize toxicity that may interfere with delivery of drug or radiation. In the future, more effective, less toxic chemotherapy drugs and better radiation techniques should improve outcomes for patients with unresectable stage III non-small cell lung cancer (NSCLC).