Crizotinib (PF02341066) as a ALK /MET inhibitor- Special Emphasis as a Therapeutic Drug Against Lung Cancer.

There are a number of molecular abnormalities that can occur in normal cells to induce a malignant phenotype. Recently, the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) has been shown to have gain-of-function when partnered with different proteins. As an example, on chromosome 2p, with inversion, there is translocation with generation of EML4-ALK tyrosine kinase in lung cancer. In a phase I trial, EML4-ALK patients were selected to determine the response to a potent small molecule tyrosine kinase inhibitor crizotinib (previously identified as PF02341066). Dramatic durable responses were observed with crizotinib at 250 mg twice a day (orally). Interestingly, crizotinib also has activity against MET receptor tyrosine kinase. We have previously shown that MET can be overexpressed, sometimes mutated, or sometimes amplified in lung cancer. Thus, this review will emphasize the characteristics of crizotinib, and detail the clinical experience.

Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck: The Active8 Randomized Clinical Trial.

Importance: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity. Objective: To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy. Design, Setting, and Participants: The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017. Interventions: Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks. Main Outcomes and Measures: Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety. Results: Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02). Conclusions and Relevance: Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients. Trial Registration: ClinicalTrials.gov identifier: NCT01836029.

Predictors of distant metastasis in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal cancer is associated with favorable outcomes, prompting investigations into treatment deintensification. The purpose of this study was for us to present the predictors of distant metastases in patients with HPV-positive oropharyngeal cancer treated with cisplatin-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (bio-RT). METHODS: In patients with stage III to IVb HPV-positive oropharyngeal cancer, the Kaplan-Meier analysis was used to calculate distant metastases rates. Univariate analysis (UVA) and multivariate analysis (MVA) were used to identify factors associated with distant metastases. RESULTS: Increased distant metastases rates were noted in active smokers versus never/former smokers (22% vs 5%), T4 vs T1 to T3 (15% vs 6%), and cetuximab-based bio-RT versus CRT (23% vs 5%). All remained significant on MVA. CONCLUSION: T4 tumors and active smokers have substantial rates of distant metastases, and trials investigating intensified systemic therapies may be considered. Higher rates of distant metastases observed with concurrent cetuximab are hypothesis generating, but further data are needed. © 2017 Wiley Periodicals, Inc. Head Neck 39: 940-946, 2017.

Split-Course Accelerated Hypofractionated Radiotherapy (SCAHRT): A Safe and Effective Option for Head and Neck Cancer in the Elderly or Infirm.

BACKGROUND: Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients. PATIENTS AND METHODS: The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis. RESULTS: Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively. CONCLUSION: In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches.

Regional control is preserved after dose de-escalated radiotherapy to involved lymph nodes in HPV positive oropharyngeal cancer.

OBJECTIVES: To analyze a cohort of patients with HPV positive, oropharyngeal squamous cell carcinoma (OPSCC) treated with lower radiation dose to clinically involved lymph nodes. MATERIALS AND METHODS: We retrospectively identified patients with HPV positive, OPSCC treated with definitive chemoradiotherapy (70-74.4Gy) to the primary site and, since a post-radiation neck dissection was planned, 54Gy to the involved nodal areas. Neck dissection was ultimately omitted in all cases due to complete response. All patients were treated with a 3 field approach with sequential boost plans. Composite plans were generated retrospectively and primary tumor and lymph node GTVs were contoured and nodes were expanded by 5mm to form a CTV. Mean dose, dose to 95% (D95) and dose to 99% (D99) were determined. RESULTS: Fifty patients treated from 2008 to 2010 with 113 involved nodes were identified. The median age was 57years, and 6%, 46%, and 48% were current, former, and never smokers. Ninety percent of patients received concurrent cisplatin based chemotherapy. Median D95 and D99 to involved nodes were 59.8Gy and 55.9Gy respectively. At a median follow up of 54.1months, two patients developed nodal failure and four developed metastatic disease. Five year loco-regional control, disease free survival and overall survival were 96%, 81% and 86% respectively. CONCLUSION: In this exploratory analysis, regional lymph node control in HPV positive oropharyngeal cancer was not compromised by dose de-escalated radiotherapy to involved nodes in the setting of concurrent cisplatin based chemotherapy.

Impaired vocal cord mobility in T2N0 glottic carcinoma: Suboptimal local control with Radiation alone.

BACKGROUND: T2 glottic cancer with impaired vocal cord mobility (T2b) is known to have higher local failure rates when compared with T2 cancers without impaired cord mobility (T2a) treated with radiotherapy (RT) alone. METHODS: In this retrospective review, we identified and compared the local control rates of 3 groups: T2aN0 treated with RT; T2bN0 treated with RT; and T2b-3N0-2 treated with chemoradiotherapy (CRT). RESULTS: The 3-year local control rate was 95.1% for T2aN0, 73.2% for T2bN0 treated with RT, and 91.5% for the CRT group (p = .01). On univariate analysis, T2bN0 disease versus T2aN0 treated with RT alone (p = .03) was significantly associated with inferior local control. CONCLUSION: Patients with glottic cancer with impaired vocal cord mobility (T2b) have a high rate of local failure with RT alone. The addition of concurrent chemotherapy should be considered for patients highly motivated toward larynx preservation and willing to accept the potential toxicity. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1832-1836, 2016.

Risk Factors Associated with Disease Recurrence in Patients with Stage III/IV Squamous Cell Carcinoma of the Oral Cavity Treated with Surgery and Postoperative Radiotherapy.

AIM: The purpose of the present study was to identify variables associated with high risk of failure in patients with locally advanced squamous cell carcinoma of the oral cavity (SCC-OC). PATIENTS AND METHODS: This retrospective study included 191 patients with stage III-IVb SCC-OC treated with post-operative radiotherapy (RT) or chemoradiotherapy (CRT) between 1995 and 2013. Disease-free (DFS) and overall survival (OS) were analyzed; variables associated with inferior DFS were identified. RESULTS: Seventy-five patients (39%) recurred. DFS and five-year OS were 52% and 54%, respectively. Poorly differentiated tumors (p=0.03), recurrent tumors (p=0.02) and high nodal ratio (p=0.02) were associated with an increased risk of recurrence. CRT was associated with improved DFS in patients with positive margins and/or extracapsular extension (p=0.021). CONCLUSION: Tumors that are recurrent, high grade, or have high nodal ratio are at risk of recurrence. Presence of these disease features should be taken into consideration for better risk stratification.

Severe late dysphagia and cause of death after concurrent chemoradiation for larynx cancer in patients eligible for RTOG 91-11.

PURPOSE: The long-term results of RTOG 91-11 suggested increased deaths not attributed to larynx cancer after concomitant chemoradiotherapy (CRT) despite no apparent increase in late effects. Because the timing of events was not reported by RTOG 91-11, one possibility is that severe late dysphagia (SLD) develops beyond five years and leads to unreported treatment-related deaths. Here we explore the timing of SLD after CRT. METHODS: Patients who would have met eligibility criteria for RTOG 91-11 and were treated with CRT between 1993 and 2013 were identified. Events occurring beyond 3months after treatment and suggestive of SLD were recorded including esophageal stricture dilations, hospital admissions for aspiration pneumonia or feeding-tube insertion. Feeding-tube dependence beyond one year was also considered SLD. The cumulative incidence of SLD and its components was quantified using Gray's competing risk analysis with recurrence or death considered competing risks. RESULTS: Eighty-four patients were included with a median follow-up of 43months. The 5-year overall survival was 70% (95% CI 58-80%). No death was directly a result of treatment-induced late dysphagia. The 5-year incidence of SLD was 26.5%. While 15 of 18 (83%) first stricture dilations occurred within 5years after CRT, 3 of 5 (60%) aspiration admissions and 5 of 8 late feeding tube insertions occurred beyond five years from CRT. CONCLUSIONS: SLD is common after CRT for larynx cancer and can occur beyond 5years from the end of treatment, emphasizing the importance of survivorship follow-up. Despite the incidence of SLD, death related to dysphagia is uncommon.

Impact of feeding tube choice on severe late dysphagia after definitive chemoradiotherapy for human papillomavirus-negative head and neck cancer.

BACKGROUND: Severe late dysphagia is common after chemoradiotherapy for cancers of the larynx and oropharynx. Options for reduction of severe late dysphagia are limited for human papillomavirus (HPV)-negative patients. In this study, the role of feeding tube choice in severe late dysphagia is investigated. METHODS: Patients disease-free after chemoradiotherapy for HPV-negative cancers of the laryngopharynx who received a feeding tube on-treatment were identified. The incidence of severe late dysphagia after reactive nasogastric (R-NG), proactive or reactive percutaneous gastrostomy (P-PEG or R-PEG) was assessed using log-rank and Cox analyses. RESULTS: Seventy-eight patients received a feeding tube on-treatment and remained disease-free. Median follow-up was 64 months. The 5-year incidence of severe late dysphagia was 30.8% in the R-NG cohort (n = 36), 56.4% in the R-PEG (n = 17; p = .193), and 60.9% in the P-PEG (n = 25; p = .016) cohorts. On multivariate analysis, percutaneous gastrostomy (PEG) feeding was independently associated with an increased rate of severe late dysphagia. CONCLUSION: R-NG use during chemoradiotherapy is associated with less severe late dysphagia and is preferred over PEG. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1054-E1060, 2016.

Pharmacotherapy of head and neck cancer.

INTRODUCTION: There are over 55,000 new cases of head and neck cancer diagnosed annually in the United States. Historically surgical resection was the standard of care, but due to vital structures in the head and neck region this led to severe morbidity. The integration of pharmacotherapy has rapidly expanded over the years into a multimodality treatment paradigm for locally advanced head and neck cancer, allowing organ-sparing treatment approaches. Here we discuss the various approaches and settings in which chemotherapy can be incorporated into the management of head and neck squamous cell carcinoma (HNSCC). AREAS COVERED: Chemotherapy in HNSCC can be administered in several different treatment circumstances: in the metastatic setting for palliation of symptoms and prolongation of survival, before definitive local treatment (induction), as part of definitive treatment simultaneously with radiation (concurrent) or after definitive local therapy (adjuvant). EXPERT OPINION: The incorporation of chemotherapy into the management of patients with head and neck cancer has allowed organ preservation approaches and improved survival. Because of the toxicities of chemotherapy, it is imperative that chemotherapy is only administered to the appropriate patient population who are more likely to benefit. Cisplatin 100 mg/m(2) given in combination with radiation in the non-metastatic setting is the most widely tested regimen and remains the reference regimen. Cetuximab is also an alternative, but there is no data to support the use of cetuximab in a laryngeal preservation approach or in the postoperative setting.

Early and Severe Radiation Toxicity Associated with Concurrent Sirolimus in an Organ Transplant Recipient with Head and Neck Cutaneous Squamous Cell Carcinoma: A Case Report.

We present a case of a 71-year-old man with a history of liver transplantation who was treated with adjuvant radiotherapy with concurrent cisplatin for recurrent cutaneous squamous cell carcinoma of the head and neck. The patient was transitioned from tacrolimus to sirolimus for immunosuppression immediately prior to the start of radiation therapy, with the goal of reducing the risk for further skin cancer recurrence. The patient developed severe normal tissue toxicity, disproportionate to the dose delivered. He was diagnosed with Grade 4 esophagitis and mucositis after just 2,400 cGy in 12 fractions (planned 6,400 cGy in 32 fractions), requiring cessation of therapy. Six months later, the patient was diagnosed with local recurrence and distant metastases in the lung, and unfortunately passed away one month later. Randomized data have demonstrated the anti-neoplastic benefit of sirolimus. Pre-clinical studies and animal models have suggested that sirolimus may be a radiation sensitizer; however, the literature is limited regarding the clinical translation of these biologic findings. The case we presented reflects that concurrent radiation therapy with sirolimus may enhance the cytotoxic effects of radiation therapy and contribute to dose-limiting toxicity. Certainly, further study is necessary to explore this observation.

Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy.

IMPORTANCE: Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS: All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS: Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

In squamous cell head and neck cancer: which platinum, how much and how often?

Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. Patients who present with locally advanced disease are usually treated with a combined modality approach, often including chemotherapy, and frequently using the platinum agents cisplatin or carboplatin. In locally advanced head and neck squamous cell carcinoma, carboplatin and cisplatin have both been found to produce a survival benefit when added to radiation therapy. Although it appears that cisplatin may be more active, carboplatin is better tolerated. Cisplatin has been given concurrently with radiation every 3 weeks, weekly or daily. There have been no prospective trials comparing the different cisplatin dose schedules, but a dose of 100 mg/m(2) administered every 3 weeks on days 1, 22 and 43 with concurrent standard fractionation radiation therapy is the most widely used and tested regimen. The required total dose of cisplatin is also not known, although a necessary dose threshold of 200 mg/m(2) has been suggested.

Solitary dural metastasis at presentation in a patient with untreated human papillomavirus-associated squamous cell carcinoma of the oropharynx.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is associated with high cure rates and distant metastases are rare. METHODS AND RESULTS: We report a case of a 61-year-old man presenting with acute left-sided weakness. An enhancing dural mass was noted and resected. Histology revealed p16-positive SCC. Further workup revealed a p16-positive right tonsillar primary with ipsilateral nodal disease and was classified as T2N2bM1. The patient underwent whole brain irradiation and definitive chemoradiation with curative intent. Complete clinical response was achieved and the patient continues to be disease-free 6 months posttreatment. CONCLUSION: HPV-associated oligometastatic oropharyngeal SCC is a rare entity that may have a unique natural history and behavior. Given the excellent treatment response and prognosis of HPV-positive disease in general, these patients may be appropriate for definitive treatment approaches.

The role of chemotherapy in locally advanced head and neck squamous cell carcinoma.

The role of chemotherapy in multimodality treatment for locally advanced head and neck squamous cell carcinoma, although firmly established, presents several unresolved issues. Concomitant platinum-based chemoradiation (CRT) is a standard treatment for unresectable, resectable but nonsurgically treated, and postoperative high-risk patients with locally advanced head and neck squamous cell carcinoma. However, no clear conclusion can be drawn regarding the optimal platinum compound or combinations to use, the type of schedule, and number of cycles (ie, platinum total dose) to be delivered. Cetuximab administered concomitantly with radiotherapy has not been directly compared with CRT but offers a potential different approach using a noncytotoxic systemic agent. In the organ preservation setting, CRT, although yielding a superior 5-year larynx preservation rate, showed similar outcomes to induction chemotherapy (IC) followed by radiation in terms of 5-year laryngectomy-free survival and overall survival, with a higher incidence of grade 3-4 mucositis. The role of IC in nonorgan preservation programs has not yet been established. Phase III trials comparing concomitant CRT versus IC followed by CRT are ongoing with results anticipated in the near future.