ABSTRACT
PURPOSE: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has continually increased during the past several decades. Using transoral robotic surgery (TORS) significantly improves functional outcomes relative to open surgery for OPSCC. However, TORS limits tactile feedback, which is often the most important element of cancer surgery. Fluorescence guided surgery (FGS) strategies to aid surgeon assessment of malignancy for resection are in various phases of clinical research but have the greatest potential impact for improving patient care when the surgeon has limited tactile feedback, such as during TORS. Here, we assessed the feasibility of intraoperative fluorescence imaging using panitumumab-IRDye800CW (PAN800) during TORS in OPSCC patients. PATIENTS AND METHODS: 12 consecutive patients with OPSCC were enrolled as part of a non-randomized, prospective, phase II FGS clinical trial using PAN800. TORS was performed with an integrated robot camera for surgeon assessment of fluorescence. Intraoperative and ex vivo fluorescence signals in tumors and normal tissue were quantified and correlated with histopathology. RESULTS: Intraoperative robot fluorescence views delineated OPSCC from normal tissue throughout the TORS procedure (10.7 mean tumor-to-background ratio), including in tumors with low expression of the molecular target. Tumor-specific fluorescence was consistent with surgeon-defined tumor borders requiring resection. Intraoperative robot fluorescence imaging revealed an OPSCC fragment initially overlooked during TORS based on brightfield views, further substantiating the clinical benefit of this FGS approach. CONCLUSIONS: Results from this OPSCC patient cohort support further clinical assessment of FGS during TORS to aid resection of solid tumors.
ABSTRACT
PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.
Subject(s)
Carcinoma, Transitional Cell , Immunoconjugates , Urinary Bladder Neoplasms , Humans , Antineoplastic Agents , Carcinoma, Transitional Cell/drug therapy , Immunoconjugates/adverse effects , Immunoconjugates/pharmacokinetics , Urinary Bladder Neoplasms/drug therapyABSTRACT
AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-ß receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-ß. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.
The purpose of this study is to find out more about the experimental oncolytic virus called AdAPT-001 that has been designed to selectively eliminate cancer cells. The virus is also designed to make a particular protein called a TGF-ß trap, which neutralizes TGF-ß, an overproduced chemical in cancer cells that puts the immune system into a comatose state. This article discusses a clinical trial called BETA PRIME for patients with no other standard treatment options. The trial will explore different doses of AdAPT-001 both alone and in combination with an approved checkpoint inhibitor or another immunotherapy, which blocks the 'off' signal on immune cells, to determine the safest and best dose. Clinical Trial Registration: NCT04673942 (ClinicalTrials.gov).
Subject(s)
Neoplasms , Oncolytic Virotherapy , Animals , Cell Line, Tumor , Clinical Trials, Phase I as Topic , Cytokines , Humans , Immunoglobulins , Immunotherapy , Mice , Neoplasms/drug therapy , Receptors, Transforming Growth Factor beta , Transforming Growth Factor betaABSTRACT
BACKGROUND: Evidence on distribution of cardiovascular disease (CVD) risk factors in patients with head and neck squamous cell carcinoma (HNSCC) is limited. We assessed disparities in prevalence and incidence of CVD risk factors in patients with HNSCC. METHODS: Electronic health records (EHR) data on 2262 patients with HNSCC diagnosed between 2012 and 2018 at a NCI-designated cancer center were included. Prevalence of CVD risk factors at baseline and incidence at 1-year post HNSCC diagnosis were assessed using logistic and robust Poisson regression, respectively. RESULTS: At baseline, 31.72% white patients with HNSCC had dyslipidemia, compared to 24.29% blacks (p < 0.008); diabetes was more prevalent in blacks (p < 0.027). Odds of ≥1 prevalent CVD clinical risk factor at baseline was lower in blacks (OR, 95%CI: 0.71, 0.54-0.93) and in rural patients (OR, 95%CI: 0.70, 0.58-0.85). At 1 year, risk of incident diabetes was higher in rural patients (RR, 95%CI: 1.63, 1.21-2.19). CONCLUSIONS: Demographic disparities were observed in distribution of CVD risk factors in patients with HNSCC.
Subject(s)
Cardiovascular Diseases , Head and Neck Neoplasms , Cardiovascular Diseases/epidemiology , Head and Neck Neoplasms/epidemiology , Heart Disease Risk Factors , Humans , Risk Factors , Squamous Cell Carcinoma of Head and Neck/epidemiologyABSTRACT
Background: Risk of incident cardiovascular disease (CVD) in head and neck squamous cell carcinoma (HNSCC) patients is under-reported. We assessed the association of HNSCC-related factors and traditional risk factors with 1- and 5-year CVD risk in HNSCC patients without prevalent CVD at cancer diagnosis. Methods: A clinical cohort of 1,829 HNSCC patients diagnosed between 2012 and 2018, at a National Cancer Institute (NCI)-designated cancer center was included. Information on HNSCC-related factors [HNSCC anatomical subsite, stage at diagnosis, treatment, and tumor human papillomavirus (HPV) status] were extracted from the tumor registry. Data on traditional risk factors (hypertension, dyslipidemia, diabetes, tobacco smoking status, and obesity) were extracted from the electronic health records system (EHR) at baseline (HNSCC diagnosis). A composite of ischemic heart disease, heart failure, and ischemic stroke was the outcome of interest in time to event analysis. Hazard ratio (HR) (95% CI) were reported with death as a competing risk. Results: In patients diagnosed with HNSCC, 10.61% developed incident CVD events by 1-year post cancer diagnosis. One-year CVD risk was lower in patients using antihypertensive medications at baseline, compared to patients without baseline hypertension [HR (95% CI): 0.41 (0.24-0.61)]. One-year CVD risk was high in patients receiving HNSCC surgery. Patients receiving radiation therapy had a higher 5-year CVD risk than surgery patients [HR (95% CI): 2.17 (1.31-3.04)]. Patients using antihypertensive medications had a lower 5-year CVD risk than patients without baseline hypertension [HR (95% CI): 0.45 (0.22-0.75)]. Older age and diabetes were associated with increased 1- and 5-year CVD risk. HPV-negative patients were older (p 0.006) and had a higher 5-year cumulative incidence of CVD (p 0.013) than HPV-positive patients. Conclusion: Traditional risk factors and cancer-related factors are associated with CVD risk in HNSCC patients. Future research should investigate the role of antihypertensive medications in reducing CVD risk in HNSCC patients.
ABSTRACT
BACKGROUND: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. METHODS: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. RESULTS: Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. CONCLUSIONS: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacokinetics , Disease Management , Drug Monitoring , Female , Humans , Lapatinib/administration & dosage , Lapatinib/pharmacokinetics , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Pilot Projects , Treatment Outcome , Triple Negative Breast Neoplasms/diagnostic imagingABSTRACT
OBJECTIVES: Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab. METHODS: Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m2, paclitaxel 175 mg/m2, and cyclophosphamide 600 mg/m2, with concurrent bevacizumab every 2 weeks without growth factor support. RESULTS: Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive. CONCLUSIONS: The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.
Subject(s)
Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Bevacizumab/therapeutic use , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Combined Modality Therapy/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Female , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/therapeutic use , Pilot ProjectsABSTRACT
Background: Rurality, race, and age at diagnosis are important predictors in head and neck cancer (HNC) prognosis. However, literature on the associations of rurality and race with age at HNC diagnosis is limited. Data on geographical, racial, and gender disparities in young HNC patients (diagnosed ≤45 years) are also scarce. Materials and Methods: This retrospective study assesses rural-urban, racial, and gender disparities in age at HNC diagnosis, using electronic medical records (Cerner) data of 4258 HNC patients (1538 residing in rural counties and 2720 in urban counties) from National Cancer Institute-designated cancer center in Alabama. Rurality was defined based on 2010 U.S. Census Bureau's rural-urban classification. Logistic regression was used to assess the association of young HNC diagnosis with demographical, behavioral, and clinical variables. ArcGIS 10.2 was used to map geospatial distribution of age and population-adjusted HNC case across rural and urban counties. Results: Patients from rural counties were less likely to be diagnosed at younger age (≤45 years) compared with urban counties (odds ratio [OR] [95% confidence interval (CI)]: 0.74 [0.58-0.93]). Most patients present at stage III/IV (64.9% in rural and 60.2% in urban). Compared with white patients, black patients were 70% more likely to get diagnosed at a young age (95% CI: 1.23-2.35). Young patients were more likely to be females and blacks compared with older patients (p<0.0001). Among oral cavity cancer patients, rural patients were 51% less likely to get diagnosed at young age compared with urban patients (95% CI: 0.27-0.89). Conclusions: Head and neck cancer screening is not routinely conducted so most show up at later stage of cancer. There is also evidence of disparities in age at HNC diagnosis based on rurality, race, and gender; targeted screening can help in reducing these disparities.
ABSTRACT
In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.
Subject(s)
Cancer Pain/diagnosis , Cancer Pain/therapy , Neoplasms/complications , Pain Management , Adult , Age Factors , Cancer Pain/etiology , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , HumansABSTRACT
Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which limited data exist to guide treatment decisions. With the advent of advanced molecular testing and tumor genomic profiling, clinicians now have the ability to identify potential therapeutic targets in difficult-to-treat cancers such as SDC. This report presents a male patient with widely metastatic SDC found on targeted next-generation sequencing to have a BRAF p.V600E mutation. He experienced a prolonged and robust response to first-line systemic chemotherapy with dabrafenib and trametinib. During his response interval, new data emerged to justify subsequent treatment with both an immune checkpoint inhibitor and androgen blockade after his disease progressed. To our knowledge, this is the first report of frontline BRAF-directed therapy eliciting a response in metastatic SDC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/therapy , MAP Kinase Kinase Kinases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Salivary Gland Neoplasms/therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma/diagnostic imaging , Carcinoma/genetics , Carcinoma/secondary , Chemoradiotherapy, Adjuvant/methods , Humans , Male , Middle Aged , Mutation , Neck Dissection/methods , Palliative Care/methods , Parotid Gland/pathology , Positron Emission Tomography Computed Tomography , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Salivary Ducts/pathology , Salivary Ducts/surgery , Salivary Gland Neoplasms/diagnostic imaging , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/pathology , Treatment OutcomeABSTRACT
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.
Subject(s)
Antiemetics/therapeutic use , Vomiting/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzodiazepines/therapeutic use , Granisetron/therapeutic use , Humans , Neoplasms/complications , Neoplasms/therapy , Olanzapine , Serotonin Antagonists/therapeutic use , Vomiting/etiology , Vomiting/prevention & controlABSTRACT
Integration and optimization of active systemic agents and radiosensitizers into the therapeutic regimen for head and neck cancer remains a topic of active investigation. Recent trials have not consistently supported the use of induction chemotherapy. There are several clinical scenarios in which there is a strong rationale for induction chemotherapy, such as larynx preservation, unfavorable sites and bulky locally advanced disease. The increasing prevalence of HPV-positive malignancies, impacts both interpretation of clinical research and the design of future trials. In the broad spectrum of this disease the prognosis is often dismal, with substantial room for improvement over current therapy. In the face of conflicting clinical data, we address the question of whether there remains a role for induction chemotherapy.
Subject(s)
Head and Neck Neoplasms/drug therapy , Induction Chemotherapy/methods , HumansABSTRACT
PURPOSE: Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer. EXPERIMENTAL DESIGN: A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology. RESULTS: There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels. CONCLUSIONS: We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.
Subject(s)
Carcinoma, Squamous Cell/surgery , Cetuximab/administration & dosage , Fluorescent Dyes/administration & dosage , Head and Neck Neoplasms/surgery , Indoles/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/pathology , Cetuximab/adverse effects , ErbB Receptors , Female , Fluorescent Dyes/adverse effects , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Male , Middle Aged , Optical Imaging , Radiography , Squamous Cell Carcinoma of Head and NeckABSTRACT
BACKGROUND: The utility of definitive radiotherapy (RT) for locoregionally advanced squamous cell carcinoma (SCC) of the larynx or hypopharynx in the setting of thyroid or cricoid cartilage invasion (TCCI) is controversial. A retrospective review of our experience was performed. METHODS: Our institutional database of patients with SCC of the head and neck treated with radiotherapy (90% received concurrent systemic therapy) between 1995 and 2009 was queried. We identified 87 patients with T3-4 laryngeal or T4 hypopharyngeal cancer for whom initial head and neck imaging was available for review. Imaging of all patients was reviewed by a single radiologist specializing in neuroradiology. The presence and extent of TCCI was determined and used for stratification. RESULTS: Median follow-up was 34 months. TCCI was found in 25 (29%) patients, eight limited to the inner cortex and another 17 involving both cortices. Local control (LC) was not significantly affected by TCCI limited to the inner cortex. However, TCCI involving both cortices was correlated with diminished LC at 2 years compared to the group of patients with no or minor invasion (55% vs. 81%, p=0.045). However, TCCI involving both cortices was not associated with significantly reduced rates of survival with a functional larynx, or overall survival (OS). CONCLUSIONS: Our results suggest that the rate of LC of T3-4 laryngeal or T4 hypopharyngeal SCC treated with definitive RT is not affected by TCCI of the inner cortex. Although decreased LC was significantly associated with TCCI involving both cortices, this factor did not appear to result in reduced rates of survival with a functional larynx or OS. Therefore, organ preservation may remain an option in these patients.
Subject(s)
Carcinoma, Squamous Cell/pathology , Cricoid Cartilage/pathology , Head and Neck Neoplasms/pathology , Hypopharyngeal Neoplasms/pathology , Laryngeal Neoplasms/pathology , Thyroid Cartilage/pathology , Thyroid Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/radiotherapy , Databases, Factual , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/radiotherapy , Humans , Hypopharyngeal Neoplasms/mortality , Hypopharyngeal Neoplasms/radiotherapy , Laryngeal Neoplasms/mortality , Laryngeal Neoplasms/radiotherapy , Male , Middle Aged , Prognosis , Retrospective Studies , Squamous Cell Carcinoma of Head and Neck , Thyroid Neoplasms/mortality , Tomography, X-Ray Computed/methods , Treatment OutcomeABSTRACT
Advances in cancer genomics have led to the recognition of a growing number of high-penetrance single-gene cancer predisposition syndromes. Frequently, the suspicion for a hereditary syndrome is raised by a strongly positive family history. However, other features, such as younger-than-usual age at diagnosis and rare histology should also prompt consideration of a genetic syndrome. Common malignancies frequently show a positive family history without an eponymous syndrome being recognized. This article reports on a case with an unusual constellation of malignancies with distinctive pathologies, which raised suspicion for an eponymous cancer pre-disposition syndrome. Absent a positive family history, a de novo mutation-an alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell of one of the parents or in the fertilized ovum-was suspected. The authors discuss indications for genetic counseling and testing, limitations, and the evidence that supports the recommendations as formulated by working groups and the NCCN. Most frequently, these recommendations are reasonable statements based on the natural history of the disease, but without population-based studies for many rare syndromes, the actual penetrance, variable expressivity, and actual associated cancer risk are unknown.
Subject(s)
Neoplasms/diagnosis , Neoplasms/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Female , Genetic Counseling , Genetic Predisposition to Disease , Genetic Testing , Humans , Middle Aged , Neoplasms/drug therapy , Neoplastic Syndromes, Hereditary/drug therapyABSTRACT
BACKGROUND: Altered fractionated radiotherapy (RT) has been shown to improve locoregional control (LRC) and overall survival (OS) in squamous cell cancer of the head and neck (SCCHN). We investigated patient outcomes using a new parameter: the average weekly dose (AWD). METHODS: The medical records of 601 patients who received definitive RT for SCCHN were reviewed. AWD was calculated by dividing the total dose in Gray (Gy) by overall treatment time in weeks, and assessed for predictive value. RESULTS: Various standard RT fractionation schedules were used. An AWD >10.0 Gy was associated with improved LRC at 2 years for patients treated with RT alone (80.9% vs 60.9%; p = .006), but not for those treated with concurrent chemoradiation (75.3% vs 77.3%; p = .77). Nonsignificant increases in late dysphagia were seen with AWD >10.0 Gy. CONCLUSION: An AWD of >10 Gy was found to be beneficial for RT alone regimens but not chemoradiotherapy regimens.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Chemoradiotherapy/methods , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cohort Studies , Databases, Factual , Disease-Free Survival , Dose Fractionation, Radiation , Dose-Response Relationship, Radiation , Female , Follow-Up Studies , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Retrospective Studies , Risk Assessment , Squamous Cell Carcinoma of Head and Neck , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor-positive breast cancer. PATIENTS AND METHODS: Patients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy. RESULTS: Twenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks (P < .0036). CONCLUSION: Combination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Bevacizumab , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Letrozole , Middle Aged , Neoplasm Staging , Nitriles/administration & dosage , Nitriles/adverse effects , Pilot Projects , Positron-Emission Tomography , Postmenopause , Receptors, Estrogen/biosynthesis , Receptors, Estrogen/genetics , Receptors, Progesterone/biosynthesis , Receptors, Progesterone/genetics , Triazoles/administration & dosage , Triazoles/adverse effectsABSTRACT
PURPOSE: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients. EXPERIMENTAL DESIGN: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics. RESULTS: Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67. CONCLUSIONS: PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.
Subject(s)
Benzamides/pharmacology , Benzamides/pharmacokinetics , Diphenylamine/analogs & derivatives , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Diphenylamine/pharmacokinetics , Diphenylamine/pharmacology , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Mitogen-Activated Protein Kinase Kinases/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Survival Rate , Tissue Distribution , Treatment OutcomeSubject(s)
Breast Neoplasms/therapy , Algorithms , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Aromatase Inhibitors/therapeutic use , Breast/radiation effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Combined Modality Therapy , Female , Humans , Lymphatic Metastasis , Mastectomy , Neoadjuvant Therapy , Neoplasm Invasiveness , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/metabolism , Postmenopause , Premenopause , Randomized Controlled Trials as Topic , Receptor, ErbB-2/metabolism , Selective Estrogen Receptor Modulators/therapeutic use , Sentinel Lymph Node Biopsy , Tamoxifen/therapeutic use , TrastuzumabABSTRACT
PURPOSE: The use of altered fractionation radiotherapy (RT) regimens, as well as concomitant chemotherapy and RT, to intensify therapy for locally advanced head-and-neck cancer can lead to increased rates of long-term dysphagia. METHODS AND MATERIALS: We identified 122 patients who had undergone definitive RT for locally advanced head-and-neck cancer, after excluding those who had been treated for a second or recurrent head-and-neck primary, had Stage I-II disease, developed locoregional recurrence, had <12 months of follow-up, or had undergone postoperative RT. The patient, tumor, and treatment factors were correlated with a composite of 3 objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy tube dependence at the last follow-up visit; aspiration on a modified barium swallow study or a clinical diagnosis of aspiration pneumonia; or the presence of a pharyngoesophageal stricture. RESULTS: A composite dysphagia outcome occurred in 38.5% of patients. On univariate analysis, the primary site (p = 0.01), use of concurrent chemotherapy (p = 0.01), RT schedule (p = 0.02), and increasing age (p = 0.04) were significantly associated with development of composite long-term dysphagia. The use of concurrent chemotherapy (p = 0.01), primary site (p = 0.02), and increasing age (p = 0.02) remained significant on multivariate analysis. CONCLUSION: The addition of concurrent chemotherapy to RT for locally advanced head-and-neck cancer resulted in increased long-term dysphagia. Early intervention using swallowing exercises, avoidance of nothing-by-mouth periods, and the use of intensity-modulated RT to reduce the dose to the uninvolved swallowing structures should be explored further in populations at greater risk of long-term dysphagia.