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Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer
Cripps, C.
Winquist, E.
Devries, M.C.
Stys–Norman, D.
Gilbert, R.
Current Oncology
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
Related Articles
Treatment of Recurrent Metastatic Head and Neck Cancer: Focus on Cetuximab
Patel, Akshar N.
Mehnert, Janice M.
Kim, Sung
Clinical Medicine Insights. Ear, Nose and Throat
EGFR belongs to the ErbB family of receptor tyrosine kinases and is associated with worse prognosis in head and neck squamous cell carcinoma (HNSCC). Cetuximab is a monoclonal antibody to the extracellular domain of EGFR and inhibits its downstream actions via multiple mechanisms. Besides its proven efficacy in locally advanced and incurable HNSCC, cetuximab has the distinct advantage of having a relatively tolerable side effect profile and not potentiating radiation toxicity. Though therapies for advanced HNSCC are evolving, locoregional recurrence and/or distant metastases occur in a large percentage of patients. Though some patients can be salvaged with surgery or radiation therapy, the majority are incurable, and are treated palliatively with systemic therapy. In the setting of first line therapy for recurrent/metastatic HNSCC, the EXTREME trial provided level 1 evidence that cetuximab improves overall survival when combined with cisplatinum and 5 FU. Following progression on first line chemotherapy, several phase II trials suggest that cetuximab monotherapy is a reasonable choice in this setting. Future studies should concentrate on clinical and molecular markers that may allow more personalized approaches to treating HNSCC, and combining EGFR inhibitors with other agents in a synergistic approach.
recurrent; metastatic; SCC; squamous cell carcinoma; EGFR; epidermal growth factor receptor; cetuximab
Related Articles
Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy
Machiels, Jean-Pascal H
Licitra, Lisa F
Haddad, Robert I
Tahara, Makoto
Cohen, Ezra EW
BMC Cancer
Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) receiving platinum-based chemotherapy as their first-line treatment have a dismal prognosis, with a median overall survival (OS) of ~7 months. Methotrexate is sometimes used following platinum failure or in patients not fit enough for platinum therapy, but this agent has not demonstrated any OS improvement. Targeted therapies are a novel approach, with the EGFR-targeting monoclonal antibody cetuximab (plus platinum-based chemotherapy) approved in the US and Europe in the first-line R/M setting, and as monotherapy following platinum failure in the US. However, there is still a high unmet medical need for new treatments that improve outcomes in the second-line R/M setting following failure on first-line platinum-containing regimens. Afatinib, an irreversible ErbB family blocker, was recently approved for the first-line treatment of EGFR mutation-positive metastatic non-small cell lung cancer. Afatinib has also shown clinical activity similar to cetuximab in a Phase II proof-of-concept HNSCC trial. Based on these observations, the Phase III, LUX-Head & Neck 1 study is evaluating afatinib versus methotrexate in R/M HNSCC patients following progression on platinum-based chemotherapy in the R/M setting.
Patients with progressive disease after one first-line platinum-based chemotherapy are randomised 2:1 to oral afatinib (starting dose 40 mg once daily) or IV methotrexate (starting dose 40 mg/m2 once weekly) administered as monotherapy with best supportive care until progression or intolerable adverse events. Efficacy of afatinib versus methotrexate will be assessed in terms of progression-free survival (primary endpoint). Disease progression will be evaluated according to RECIST v1.1 by investigator and independent central review. Secondary endpoints include OS, tumour response and safety. Health-related quality of life and biomarker assessments will also be performed.
If the LUX-Head & Neck 1 trial meets its primary endpoint, it will demonstrate the ability of afatinib to elicit an improved treatment benefit versus a commonly used chemotherapy agent in the second-line treatment of R/M HNSCC patients who have failed on first-line platinum-based therapy, confirm the clinical efficacy of afatinib observed in the Phase II proof-of-concept study, and establish a new standard of care for this patient population.
Afatinib; Methotrexate; Head and neck; Phase III; Recurrent; Metastatic
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Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer
Cohen, Martin H.
Chen, Huanyu
Shord, Stacy
Fuchs, Chana
He, Kun
Zhao, Hong
Sickafuse, Sharon
Keegan, Patricia
Pazdur, Richard
The Oncologist
The present cetuximab U.S. Food and Drug Administration submission seeks to expand the squamous cell head and neck cancer indication to include recurrent locoregional or metastatic disease. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil (FU), is compared to platinum-based therapy and 5-FU alone.
Learning Objectives
Compare survival outcomes among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Compare adverse event profiles among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Describe potential risk-benefit issues identified in the EU and US studies.
On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m2 intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m2/day continuous intravenous infusion days 1–4) were administered every 3 weeks. Cetuximab, 400 mg/m2 intravenously, was administered initially followed by cetuximab, 250 mg/m2 intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m2 weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability study in monkeys. Overall survival, the primary efficacy endpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64–0.98; p = .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46–0.72; p < .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50–3.60; p = .0001). Adverse reactions (≥25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia.
Cetuximab; Erbitux; Head and neck cancer; Advanced disease
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The Role of Cetuximab for the Treatment of Squamous Cell Carcinoma of the Head and Neck
Mehra, Ranee
Cohen, Roger B.
Burtness, Barbara A.
Clinical advances in hematology & oncology : H&O
Squamous cell carcinoma of the head and neck (HNSCC) while curable in many cases with surgery, radiation, and chemotherapy, remains a disease that is associated with significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated activity in this disease. Cetuximab, a monoclonal antibody, is FDA-approved in conjunction with radiation for locally advanced, potentially curable disease, and as a single agent for incurable recurrent/metastatic disease. In addition, there are more recent data showing a survival benefit for patients with recurrent/metastatic disease who were treated with a 1st-line regimen of platinum, fluorouracil and cetuximab. These promising results have had a significant impact on the standard of care for HNSCC, and have prompted further research on the role of EGFR inhibitors in the treatment of HNSCC. In the following review, we will discuss the history, mechanism, and clinical trials that pertain to the role of cetuximab in the treatment of HNSCC.
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KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer
Ontario Health Technology Assessment Series
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based and Economic Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based and Economic Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis.
The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer (mCRC) with two anti-EGFR agents, cetuximab and panitumumab. Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing.
Clinical Need: Condition and Target Population
Metastatic colorectal cancer (mCRC) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis (TNM) system or stage D in the Duke's classification system. Patients with advanced colorectal cancer (mCRC) either present with metastatic disease or develop it through disease progression.
KRAS (Kristen-RAS, a member of the rat sarcoma virus (ras) gene family of oncogenes) is frequently mutated in epithelial cancers such as colorectal cancer, with mutations occurring in mutational hotspots (codons 12 and 13) of the KRAS protein. Involved in EGFR-mediated signalling of cellular processes such as cell proliferation, resistance to apoptosis, enhanced cell motility and neoangiogenesis, a mutation in the KRAS gene is believed to be involved in cancer pathogenesis. Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR (epidermal growth factor receptor with tyrosine kinase activity) treatments such as cetuximab and panitumumab, hence, the important in evaluating the evidence on the predictive value of KRAS testing in this context.
KRAS Mutation Testing in Advanced Colorectal Cancer
Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene. Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine. It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens. Panitumumab is only indicated as a single agent after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
In Ontario, patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab. Eligibility for these treatments is based on the KRAS status of their tumour, derived from tissue collected from surgical or biopsy specimens. It is believed that KRAS status is not affected by treatments, therefore, for patients for whom surgical tissue is available for KRAS testing, additional biopsies prior to treatment with these targeted agents is not necessary. For patients that have not undergone surgery or for whom surgical tissue is not available, a biopsy of either the primary or metastatic site is required to determine their KRAS status. This is possible as status at the metastatic and primary tumour sites is considered to be similar.
Research Question
To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy.
Research Methods
Literature Search
The Medical Advisory Secretariat followed its standard procedures and on May 18, 2010, searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database.
The subject headings and keywords searched included colorectal cancer, cetuximab, panitumumab, and KRAS testing. The search was further restricted to English-language articles published between January 1, 2009 and May 18, 2010 resulting in 1335 articles for review. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters. Studies published from January 1, 2005 to December 31, 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality (AHRQ), published in 2010. In total, 14 observational studies were identified for inclusion in this EBA: 4 for cetuximab monotherapy, 7 for the cetuximab-irinotecan combination therapy, and 3 to be included in the review for panitumumab monotherapy
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 2005 to May 2010, inclusive.
Randomized controlled trials (RCTs) or observational studies, including single arm treatment studies that include KRAS testing.
Studies with data on main outcomes of interest, overall and progression-free survival.
Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy.
For the cetuximab-irinotecan evaluation, studies in which at least 70% of patients in the study received this combination therapy.
Exclusion Criteria
Studies whose entire sample was included in subsequent publications which have been included in this EBA.
Studies in pediatric populations.
Case reports, comments, editorials, or letters.
Outcomes of Interest
Overall survival (OS), median
Progression-free-survival (PFS), median.
Response rates.
Adverse event rates.
Quality of life (QOL).
Summary of Findings of Systematic Review
Cetuximab or Panitumumab Monotherapy
Based on moderate GRADE observational evidence, there is improvement in PFS and OS favouring patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation.
Cetuximab-Irinotecan Combination Therapy
There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to those with the mutation.
However, cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation, as observed effects were lower than for patients without the mutation. Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would, therefore, be regarded as hypothesis generating.
Economic Analysis
Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review. Evaluation of relative cost-effectiveness, based on a decision-analytic cost-utility analysis, assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy, panitumumab monotherapy, cetuximab in combination with irinotecan, and best supportive care.
Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options, and does not assess the cost-effectiveness of the drug treatments alone.
KRAS status is predictive of outcomes in cetuximab and panitumumab monotherapy, and in cetuximab-irinotecan combination therapy.
While KRAS testing is cost-effective for all strategies considered, it is not equally cost-effective for all treatment options.
Related Articles
Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy
Pogorzelski, M
Ting, S
Gauler, T C
Breitenbuecher, F
Vossebein, I
Hoffarth, S
Markowetz, J
Lang, S
Bergmann, C
Brandau, S
Jawad, J A
Schmid, K W
Schuler, M
Kasper, S
Cell Death & Disease
Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.
HNSCC; cetuximab; HPV; resistance; EGFR; ADCC
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Cetuximab: its unique place in head and neck cancer treatment
Specenier, Pol
Vermorken, Jan B
Biologics : Targets & Therapy
Head and neck cancer is the sixth most common cancer worldwide. At present, globally about 650,000 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. The epidermal growth factor receptor (EGFR) is almost invariably expressed in SCCHN. Overexpression of the EGFR is a strong and independent unfavorable prognostic factor in SCCHN. Cetuximab is a chimeric monoclonal antibody, which binds with high affinity to the extracellular domain of the human EGFR, blocking ligand binding, resulting in inhibition of the receptor function. It also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody dependent cell-mediated cytotoxicity). The addition of cetuximab to radiotherapy (RT) improves locoregional control and survival when compared to RT alone. The addition of cetuximab to platinum-based chemoradiation (CRT) is feasible but does not lead to an improved outcome. Cetuximab plus RT has never been compared prospectively to CRT, which therefore remains the standard treatment for patients with locoregionally advanced SCCHN for whom surgery is not considered the optimal treatment, provided they can tolerate CRT. The addition of cetuximab to platinum-based chemotherapy prolongs survival in patients with recurrent or metastatic SCCHN. The combination of a platinum-based regimen and cetuximab should be considered as the standard first line regimen for patients who can tolerate this treatment.
SCCHN; cetuximab; recurrent metastatic; locoregionally advanced; chemoradiation
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HPV & head and neck cancer: a descriptive update
Goon, Peter KC
Stanley, Margaret A
Ebmeyer, Jörg
Steinsträsser, Lars
Upile, Tahwinder
Jerjes, Waseem
Bernal-Sprekelsen, Manuel
Görner, Martin
Sudhoff, Holger H
Head & Neck Oncology
The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers.
Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality.
Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.
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A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck†
Seiwert, T. Y.
Fayette, J.
Cupissol, D.
del Campo, J. M.
Clement, P. M.
Hitt, R.
Degardin, M.
Zhang, W.
Blackman, A.
Ehrnrooth, E.
Cohen, E. E. W.
Annals of Oncology
Afatinib, an oral irreversible ErbB family blocker, showed comparable activity to cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma in this phase II trial. Further, sequential EGFR/ErbB treatment provided sustained clinical benefit in some patients, suggesting a lack of cross-resistance.
Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.
Patients and methods
An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).
A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.
Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.
afatinib; cetuximab; recurrent HNSCC; metastatic HNSCC; EGFR inhibitor therapy
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An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents
Péron, Julien
Polivka, Valentine
Chabaud, Sylvie
Poupart, Marc
Ceruse, Philippe
Ramade, Antoine
Girodet, Didier
Zrounba, Philippe
Fayette, Jérôme
BMC Cancer
The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients. The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy.
This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines.
Most patients received at least two treatment lines. Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial.
The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab.
Recurrent and/or metastatic head and neck squamous cell carcinoma; Chemotherapy; Survival analysis; Treatment outcome; Drug administration schedule
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Cost-Effectiveness of Adding Cetuximab to Platinum-Based Chemotherapy for First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer
Hannouf, Malek B.
Sehgal, Chander
Cao, Jeffrey Q.
Mocanu, Joseph D.
Winquist, Eric
Zaric, Gregory S.
PLoS ONE
To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system.
We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%.
In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab.
The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy.
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Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer
Heukelom, Jolien
Hamming, Olga
Bartelink, Harry
Hoebers, Frank
Giralt, Jordi
Herlestam, Teresa
Verheij, Marcel
Brekel, Michiel van den
Vogel, Wouter
Slevin, Nick
Deutsch, Eric
Sonke, Jan-Jakob
Lambin, Philippe
Rasch, Coen
BMC Cancer
Failure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and 89Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection.
ARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m2 for 6 weeks. Cetuximab is dosed 250mg/m2 weekly (loading dose 400 mg/m2) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment.
Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible.
Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median 89Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival.
The objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and 89Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity.
ClinicalTrials.gov Identifier: NCT01504815
Head and neck; Squamous cell carcinoma; Adaptive radiotherapy; Dose painting; Zirconium; Cetuximab; Cisplatin
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Recent results of cetuximab use in the treatment of squamous cell carcinoma of the head and neck
Perri, Francesco
Longo, Francesco
Ionna, Franco
Caponigro, Francesco
OncoTargets and therapy
Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. The role of cetuximab is paramount in several subsets of head and neck cancer. In particular, the EXTREME study has indicated cetuximab as the only drug to improve survival when associated with cisplatin and 5-fluorouracil in patients with recurrent/metastatic disease. Furthermore, cetuximab, both alone and in combination with cisplatin, is active in patients with recurrent/metastatic disease who have failed prior platinum-based chemotherapy. Cetuximab, given in association with radiation therapy, is a treatment of choice in first-line therapy of patients with locally advanced inoperable disease. In the same setting, the role of induction chemotherapy has gained considerable interest over the last few years and a number of efforts are being pursued to optimally integrate induction chemotherapy with radiation therapy plus cetuximab. The combination of cetuximab and other targeted therapies is among the most promising new perspectives for patients with head and neck cancer.
cetuximab; head and neck cancer; locally advanced; recurrent/metastatic
Related Articles
Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients
Chung, Christine H.
Seeley, Erin H.
Roder, Heinrich
Grigorieva, Julia
Tsypin, Maxim
Roder, Joanna
Burtness, Barbara A.
Argiris, Athanassios
Forastiere, Arlene A.
Gilbert, Jill
Murphy, Barbara
Caprioli, Richard M.
Carbone, David P.
Cohen, Ezra E.W.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.
Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into "good" or "poor" groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.
In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.
Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings.
Related Articles
Cetuximab Plus Platinum-Based Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Retrospective Study in a Single Comprehensive European Cancer Institution
de Mello, Ramon Andrade
Gerós, Sandra
Alves, Marcos Pantarotto
Moreira, Filipa
Avezedo, Isabel
Dinis, José
PLoS ONE
The use of cetuximab in combination with platinum (P) plus 5-fluorouracil (F) has previously been demonstrated to be effective in the treatment of metastatic squamous cell cancer of head and neck (SCCHN). We investigated the efficacy and outcome of this protocol as a first-line treatment for patients with recurrent or metastatic disease. We evaluated overall-survival (OS), progression-free-survival (PFS), overall response rate (ORR) and the treatment toxicity profile in a retrospective cohort.
Patients and Methods
This study enrolled 121 patients with untreated recurrent or metastatic SCCHN. The patients received PF+ cetuximab every 3 weeks for a maximum of 6 cycles. Patients with stable disease who received PF+ cetuximab continued to receive cetuximab until disease progressed or unacceptable toxic effects were experienced, whichever occurred first.
The median patient age was 53 (37–78) years. The patient cohort was 86.8% male. The addition of cetuximab to PF in the recurrent or metastatic setting provided an OS of 11 months (Confidential Interval, CI, 95%, 8.684–13.316) and PFS of 8 months (CI 95%, 6.051–9.949). The disease control rate was 48.9%, and the ORR was 23.91%. The most common grade 3 or 4 adverse events in the PF+ cetuximab regimen were febrile neutropenia (5.7%), skin rash (3.8%) and mucosistis (3.8%).
The results of this study suggest that cetuximab plus platinum–fluorouracil chemotherapy is a good option for systemic treatment in advanced SSCHN patients. This regimen has a well-tolerated toxicity profile.
Related Articles
Efficacy of gemcitabine and cetuximab combination treatment in head and neck squamous cell carcinoma
Molecular and Clinical Oncology
Head and neck squamous cell carcinoma (HNSCC) may be curable with surgery, radiation and chemotherapy in its early stages. However, recurrence and metastasis often prevail following primary treatment in advanced stage cases and are associated with significant morbidity and mortality. In this study we investigated the combination therapy of gemcitabine and cetuximab for HNSCC. The UM-SCC-6 and UM-SCC-23 HNSCC cell lines were analyzed following treatment with gemcitabine and cetuximab. To determine the mechanism of action of this combination treatment, the cell cycle distributions following gemcitabine and/or cetuximab treatment were analyzed by flow cytometry and apoptosis assay. Gemcitabine and cetuximab combination treatment exerted an enhanced cytotoxic effect. The cell cycle analysis demonstrated that cells accumulated in the S phase following gemcitabine treatment and G1 arrest occurred following cetuximab treatment. An increase in sub-G1 phase cells was also observed following treatment with the two drugs. In an apoptosis assay, caspase 3/7 activity was found to be higher when administering a combination of gemcitabine and cetuximab compared to each agent administered alone. Gemcitabine and cetuximab are individually effective against HNSCC and an enhanced growth inhibitory effect may be expected when these agents are used in combination.
head and neck squamous cell carcinoma; chemotherapy; cetuximab; gemcitabine; cell cycle
Related Articles
Concurrent Radiotherapy with Carboplatin and Cetuximab for the Treatment of Medically Compromised Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
Saigal, Kunal
Santos, Edgardo S.
Tolba, Khaled
Kwon, Deukwoo
Elsayyad, Nagy
Abramowitz, Matthew C.
Mandalia, Amar
Samuels, Michael Andrew
Frontiers in Oncology
Background: Cetuximab (Cx) + radiation therapy (RT) is well-tolerated and has improved survival in patients (pts) with locoregionally advanced head and neck squamous cell carcinomas (LA-HNSCC). However, its efficacy when compared to HD-DDP + RT has been questioned. At our institution, low-dose weekly carboplatin is added to Cx + RT for patients unsuitable for HD-DDP.
Methods: We reviewed records of 16 patients with LA-HNSCC treated with definitive Cx + carboplatin + RT at the University of Miami from 2007 to 2011. Median follow-up was 24 months (range: 1–69 months).
Results: Median age: 71.5 years (range: 57–90 years); 15 male, 1 female. ECOG PS 0 = 15, 1 = 1. TNM staging was: T1 = 1, T2 = 5, T3 = 8, T4 = 2; N stage: N0 = 8, N1 = 5, N2a = 2, N2b = 1. All patients received weekly carboplatin (AUC 1.5–2), Cx given conventionally and daily conventionally fractionated RT. Median total weeks of concurrent systemic therapy = 7 (range: 3–8 weeks). RT was delivered to a median total dose of 70 Gy (range 30–74 Gy). Of the 15 evaluable patients, there were: 12 CR, 2 PR, and 1 PD. There were three local in-field failures, two regional failures, and three distant failures. At last follow-up, 8/15 patients remained with NED. Three-year locoregional recurrence was 28.3% (95% CI: 7.7–53.9%). Mean percentage of weight loss was 14% (range: 6–26%). Two patients required systemic therapy dose reduction. Three patients experienced a treatment delay and three did not finish RT as planned including a patient who received only 30 Gy due to death secondary to MI during treatment.
Conclusion: In this small retrospective series, carboplatin/Cx/RT was well-tolerated and efficacious in patients unsuitable for HD-DDP having LA-HNSCC. Acute toxicities were similar to Cx + RT, likely due to the non-overlapping toxicity profiles of the two systemic agents. We hypothesize that the addition of a well-tolerated cytotoxic chemotherapy agent may improve the therapeutic ratio of Cx + RT in patients who are poor candidates for more aggressive therapies and warrants evaluation in a prospective manner.
carboplatin; cetuximab; radiation; head; neck; squamous cell carcinoma
Related Articles
Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit
Raju, Uma
Molkentine, David P
Valdecanas, David R
Deorukhkar, Amit
Mason, Kathryn A
Buchholz, Thomas A
Meyn, Raymond E
Ang, Kie-Kian
Skinner, Heath
Cancer Medicine
Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC-A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ-H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC-A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ-H2AX and 53BP1 foci. IMC-A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. Addition of IMC-A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC-A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT.
Head and neck squamous cell carcinoma; IGF-1R and EGFR signaling; radiosensitivity; tumor response to radiation
Related Articles
Rapid palliation of symptoms with platinum-based chemotherapy plus cetuximab in recurrent oral cancer: a case report
Mesía, Ricard
Palmero, Ramón
Cos, Mònica
Vilajosana, Esther
Vázquez, Silvia
Head & Neck Oncology
Symptom control is an important consideration in the choice of treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients who demonstrate objective tumour responses to platinum-based chemotherapy are more likely to have symptom relief than those who do not have such responses. A phase III trial (EXTREME) showed that adding the epidermal growth factor receptor (EGFR)-targeting IgG1 monoclonal antibody cetuximab to first-line platinum-based chemotherapy significantly prolongs progression-free and overall survival and increases response rate compared with platinum-based chemotherapy alone. We report here the case of a 60-year old female with recurrent squamous cell carcinoma of the gum who had rapid palliation of symptoms and reduction of facial disease mass following treatment with a combination of carboplatin/5-fluorouracil (5-FU) and cetuximab.
Case presentation
The patient was diagnosed with T4N0 M0 disease of the oral cavity in November 2006 and underwent surgery, with R0 resection, followed by adjuvant radiotherapy and concomitant cisplatin chemotherapy. Around 3 months later, the disease recurred and the patient had severe pain (9/10 on a visual pain scale), marked facial oedema and a palpable facial mass of 89 mm. The patient received 4 21-day cycles of carboplatin (AUC 5), 5-FU (1,000 mg/m2/day for 4 days) and cetuximab (400 mg/m2 initial dose followed by subsequently weekly doses of 250 mg/m2), with continuation of cetuximab monotherapy at the end of this time, and pain relief with topical fentanyl and oral morphine. After 7 days of treatment, pain had reduced to 2/10, with discontinuation of morphine after 4 days, and the facial mass had reduced to 70 mm. After 2 cycles of treatment, the facial mass had decreased to 40 mm. After 3 cycles of treatment, pain and facial oedema had resolved completely and a cervical computed tomography scan showed a marked reduction in tumour mass. Cetuximab monotherapy was continued uninterrupted for 7 months.
This case illustrates the rapid reduction of tumour mass and disease-associated pain and oedema that can be achieved with a combination of platinum-based chemotherapy and cetuximab in recurrent and/or metastatic SCCHN.
Related Articles
Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma
Li, Chunrong
Iida, Mari
Dunn, Emily F.
Wheeler, Deric L.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Background and Purpose
The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab and radiation–induced translocation of EGFR to the nucleus in HNSCC cell lines.
Material and Methods
We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src Family Kinases, to determine if SFKs blockade could abrogate cetuximab and radiation-induced nuclear EGFR translocation.
Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab and radiation-induced EGFR translocation to the nucleus.
The data presented in this report suggests that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.
EGFR; cetuximab; radiation; Src family kinases; dasatinib; head and neck cancer
Related Articles
Regulation of Heparin-Binding EGF-Like Growth Factor by miR-212 and Acquired Cetuximab-Resistance in Head and Neck Squamous Cell Carcinoma
Hatakeyama, Hiromitsu
Cheng, Haixia
Wirth, Pamela
Counsell, Ashley
Marcrom, Samuel R.
Wood, Carey Burton
Pohlmann, Paula R.
Gilbert, Jill
Murphy, Barbara
Yarbrough, Wendell G.
Wheeler, Deric L.
Harari, Paul M.
Guo, Yan
Shyr, Yu
Slebos, Robbert J.
Chung, Christine H.
PLoS ONE
We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).
Methodology/Principal Findings
Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.
Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
Related Articles
Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab
Wheeler, Deric L.
Iida, Mari
Kruser, Tim J.
Nechrebecki, Meghan M.
Dunn, Emily F.
Armstrong, Eric A.
Huang, Shyhmin
Harari, Paul M.
Cancer biology & therapy
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.
EGFR; cetuximab; resistance; Src-family kinases; dasatinib
Related Articles
Preclinical modeling of EGFR inhibitor resistance in head and neck cancer
Quesnelle, Kelly M.
Wheeler, Sarah E.
Ratay, Mary K.
Grandis, Jennifer R.
Cancer Biology & Therapy
The epidermal growth factor receptor (EGFR) is widely expressed in head and neck squamous cell carcinomas (HNSCC) and can activate many growth and survival pathways within tumor cells. Despite ubiquitous EGFR expression, therapies targeting the receptor are only modestly effective in the treatment of HNSCC. A consistent mechanism of resistance to EGFR targeting agents has not yet been identified in HNSCC likely due, in part, to the paucity of preclinical models. We assessed the in vitro and in vivo responses of a panel of 10 genotypically validated HNSCC cell lines to the EGFR inhibitors erlotinib and cetuximab to determine their validity as models of resistance to these agents. We defined a narrow range of response to erlotinib in HNSCC cells in vitro and found a positive correlation between EGFR protein expression and erlotinib response. We observed cross-sensitivity in one HNSCC cell line, 686LN, between erlotinib and cetuximab in vivo. We attempted to generate models of cetuximab resistance in HNSCC cell line-derived xenografts and heterotopic tumorgrafts generated directly from primary patient tumors. While all 10 HNSCC cell line xenografts tested were sensitive to cetuximab in vivo, heterotopic patient tumorgrafts varied in response to cetuximab indicating that these models may be more representative of clinical responses. These studies demonstrate the limitations of using HNSCC cell lines to reflect the heterogeneous clinical responses to erlotinib and cetuximab, and suggest that different approaches including heterotopic tumorgrafts may prove more valuable to elucidate mechanisms of clinical resistance to EGFR inhibitors in HNSCC.
HNSCC; cetuximab; cetuximab resistance; epidermal growth factor receptor (EGFR); erlotinib; erlotinib resistance; heterotopic tumorgraft; xenograft
Related Articles
Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas
Mroz, Edmund A.
Tward, Aaron M.
Hammon, Rebecca J.
Ren, Yin
Rocco, James W.
PLoS Medicine
Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.
Methods and Findings
Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.
To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.
In this study, Rocco and colleagues examine data collected as part of a large, multi-institutional study, to validate a measure of tumor heterogeneity called MATH and determine whether intra-tumor heterogeneity is itself related to mortality.
Editors' Summary
Normally, the cells in human tissues and organs only reproduce (a process called cell division) when new cells are needed for growth or to repair damaged tissues. But sometimes a cell somewhere in the body acquires a genetic change (mutation) that disrupts the control of cell division and allows the cell to grow continuously. As the mutated cell grows and divides, it accumulates additional mutations that allow it to grow even faster and eventually from a lump, or tumor (cancer). Other mutations subsequently allow the tumor to spread around the body (metastasize) and destroy healthy tissues. Tumors can arise anywhere in the body—there are more than 200 different types of cancer—and about one in three people will develop some form of cancer during their lifetime. Many cancers can now be successfully treated, however, and people often survive for years after a diagnosis of cancer before, eventually, dying from another disease.
Why Was This Study Done?
The gradual acquisition of mutations by tumor cells leads to the formation of subpopulations of cells, each carrying a different set of mutations. This "intra-tumor heterogeneity" can produce tumor subclones that grow particularly quickly, that metastasize aggressively, or that are resistant to cancer treatments. Consequently, researchers have hypothesized that high intra-tumor heterogeneity leads to worse clinical outcomes and have suggested that a simple measure of this heterogeneity would be a useful addition to the cancer staging system currently used by clinicians for predicting the likely outcome (prognosis) of patients with cancer. Here, the researchers investigate whether a measure of intra-tumor heterogeneity called "mutant-allele tumor heterogeneity" (MATH) is related to mortality (death) among patients with head and neck squamous cell carcinoma (HNSCC)—cancers that begin in the cells that line the moist surfaces inside the head and neck, such as cancers of the mouth and the larynx (voice box). MATH is based on whole-exome sequencing (WES) of tumor and matched normal DNA. WES uses powerful DNA-sequencing systems to determine the variations of all the coding regions (exons) of the known genes in the human genome (genetic blueprint).
What Did the Researchers Do and Find?
The researchers obtained clinical and WES data for 305 patients who were treated in 14 institutions, primarily in the US, after diagnosis of HNSCC from The Cancer Genome Atlas, a catalog established by the US National Institutes of Health to map the key genomic changes in major types and subtypes of cancer. They calculated tumor MATH values for the patients from their WES results and retrospectively analyzed whether there was an association between the MATH values and patient survival. Despite the patients having tumors at various subsites and being given different treatments, every 10% increase in MATH value corresponded to an 8.8% increased risk (hazard) of death. Using a previously defined MATH-value cutoff to distinguish high- from low-heterogeneity tumors, compared to patients with low-heterogeneity tumors, patients with high-heterogeneity tumors were more than twice as likely to die (a hazard ratio of 2.2). Other statistical analyses indicated that MATH provided improved prognostic information compared to that provided by established clinical and molecular characteristics and human papillomavirus (HPV) status (HPV-positive HNSCC at some subsites has a better prognosis than HPV-negative HNSCC). In particular, MATH provided prognostic information beyond that provided by standard disease staging among patients with mouth or laryngeal cancers.
What Do These Findings Mean?
By using data from more than 300 patients treated at multiple institutions, these findings validate the use of MATH as a measure of intra-tumor heterogeneity in HNSCC. Moreover, they provide one of the first large-scale demonstrations that intra-tumor heterogeneity is clinically important in the prognosis of any type of cancer. Before the MATH metric can be used in clinical trials or in clinical practice as a prognostic tool, its ability to predict outcomes needs to be tested in prospective studies that examine the relation between MATH and the outcomes of patients with identically treated HNSCC at specific head and neck subsites, that evaluate the use of MATH for prognostication in other tumor types, and that determine the influence of cancer treatments on MATH values. Nevertheless, these findings suggest that MATH should be considered as a biomarker for survival in HNSCC and other tumor types, and raise the possibility that clinicians could use MATH values to decide on the best treatment for individual patients and to choose patients for inclusion in clinical trials.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001786.
The US National Cancer Institute (NCI) provides information about cancer and how it develops and about head and neck cancer (in English and Spanish)
Cancer Research UK, a not-for-profit organization, provides general information about cancer and how it develops, and detailed information about head and neck cancer; the Merseyside Regional Head and Neck Cancer Centre provides patient stories about HNSCC
Wikipedia provides information about tumor heterogeneity, and about whole-exome sequencing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information about The Cancer Genome Atlas is available
A PLOS Blog entry by Jessica Wapner explains more about MATH
Related Articles
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Mohawk Superfine ULTRAWHITE Smooth - 90C 23X35 (243 GSM 584X889) - 500 PK
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Mohawk Superfine Folio Paper
Superfine, Soft, luxurious. Mohawk Superfine inspires great design. A highly refined, traditional text and cover paper, Superfine is chosen by designers for its superb formation, archival quality, and timeless appeal. The paper features three perfectly tuned white shades and a comprehensive selection of weights and finishes.
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Despite The Spa's popularity—it was voted the area's best day spa by the readers of The Summerville Journal Scene in 2013—inside, it's quite tranquil and intimate. Even before treatments begin, the staff strives to make each client feel at ease, both through personal attention and the spa's quiet, cozy ambiance. Of course, the real relaxation happens in the treatment room. Massage therapists ease tension through modalities ranging from simple Swedish strokes to bamboo massage, which uses rolling, kneading, and crisscross movements from warm bamboo stalks to release tightness and keep backs from sprouting panda fur. Facials and body treatments purify pores to leave skin smooth and hydrated, and hand and foot treatments pamper extremities with filing, callus treatments, spa masques, and hot towels.
92% of 254 customers recommend
"A very nice and preaceful environment. I recommend it."
"Very cute place and outstanding service, my massage was out of this world"
"Great massage!! Ended with complimentary gourmet chocolates covered strawberries and sparkling cider in the recovery area. Very relaxing and friendly. A++++"
205 East 2nd North St.
Summerville, SC 29483
+18437258312Get Directions


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LE MAS CARAIBES... one of the most extraordinary views of the island!
From $2,500 / week
Description from the manager
Description from the manager
Bedrooms: 3/
Bathrooms: 3/
Sleeps: 6/
Type: House
7th Night Free! May 1- Sept 5, 2015Only when booked to full capacity!Cannot be combined with any other discount or promotion ! Not available on reservation already booked.Rates may vary depending on # of bedrooms rented. Please see rate table or call for details.
La Mas Caraibes feels like home away from home. This comfortable 3BR St. Martin villa rental works great for 2 couples or a small family. This French St Martin home features a stunning, unique-to-the-island 20' x 40' pool constructed from Indonesian river pebbles and edged in stainless steel to reflect the sun and water, and a custom railing, which allows you to fully enjoy the beautiful ...Read more
About the manager
About the manager
St Martin Reservation Center
St Martin Reservation Center
- Response rate: 75%
- Response time: Within a day
- Calendar updated: today
Overall rating:
4.4 / 5.0
LE MAS CARAIBES... one of the most extraordinary views of the island! Terres Basses, Saint Martin-Sint Maarten
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Box Office Report: 'Star Trek Into Darkness' Opens to Strong $31.7 Million Overseas
Paramount's aggressive campaign to improve the standing of the iconic sci-fi franchise overseas is paying off so far.
J.J. Abrams' Star Trek Into Darkness beamed up $31.7 million from only seven international markets as it began its worldwide rollout -- 70 percent ahead of the director's 2009 film.
Paramount is determined to improve the franchise's standing overseas, where Trekkie mania has never fully taken hold. To that end, the studio decided to whip up interest by opening the 3D tentpole first internationally, including in several countries where Abrams' Star Trek did the best the last time out.
PHOTOS: 'Star Trek Into Darkness' Cast Beams Up to London for World Premiere
Into Darkness, opening in the U.S. on May 16, returns Chris Pine and Zachary Quinto in the roles of James T. Kirk and Spock, respectively.
In those markets where Star Trek films have seen their strongest business -- U.K., Australia and Germany -- aggregate grosses for Into Darkness were 56 percent ahead of Abrams' 2009 reboot.
The real test for Paramount came in Mexico, New Zealand and German-speaking Switzerland, where the space-set franchise has never been especially popular. The results: Into Darkness paced 250 percent ahead of the 2009 film.
Mexico was of particular importance, since sci-fi isn't a favored genre there (it's also one of the biggest markets for 3D fare). Into Darkness took in a stellar $3 million from 573 locations, triple the opening of the 2009 film.
"That's what we were really for. Mexico is a great Barometer," says Paramount vice chairman Rob Moore. "The first movie certainly laid the groundwork for anyone who is a Star Trek fan. We want this film to cross over and create new fans."
STORY: How Paramount Plans to Break 'Star Trek's' International Curse
The U.K. led with $13.3 million from 556 locations, 50 percent better than the 2009 reboot. Into Darkness also dominated the market in Germany, grossing $7.6 million from 627 locations, 80 percent better. Australia took in $5.5 million from 263 locations, 50 percent ahead of the 2009 movie.
Paramount has taken elaborate measures in marketing Into Darkness overseas, including dispatching producer Byran Burk to share 20 minutes of footage with media and distributors in numerous countries earlier this year.
Into Darkness continues its international rollout next week, including in Russia. On May 16, it opens in China. It's already delivering strong results for Imax theaters, which took in $2.7 million over the weekend from $2.3 million.
In 2009, Star Trek grossed $257.7 million in North America and $128 million overseas, where most Hollywood tentpoles do far better.
Never miss a story. Stay up-to-date with THR's Daily Headlines.
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Tangled Feet are a physical theatre ensemble dedicated to devising original, accessible and innovative work. Our productions push the boundaries of theatrical practice, exploring and exploiting the live encounter between audience and performer, and rethinking where and how performance happens.
Tangled Feet Theatre Company Registered charity number 1143406
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Youth Charged With Discharging Fireworks In Toilet
Fire officials say a 17-year-old has been charged after fireworks were discharged in a toilet at a Westminster high school.
Maryland SPCA: It's Best To Keep Pets Indoors During Fireworks Displays
With more than 100 big fireworks shows scheduled in Maryland during the next few days, pet owners know this can be a challenging time.
Baltimore Celebrates Fourth Of July With Music, Fireworks
Baltimore is celebrating the Fourth of July with music and fireworks.
Cumberland Fireworks Go On As Originally Planned
There's good news in Cumberland for residents celebrating Independence Day: the annual fireworks show is back on at its original location.
City Police Cancel Leave, Call In Help To Ensure Safer Fourth Of July
We are just hours away from the big Fourth of July celebration at the Inner Harbor and while all eyes will be on the fireworks, police will have extra eyes on the crowds.
Preparations Underway For Massive Inner Harbor Fireworks Display
There are over 100 public fireworks displays in the coming days, but the biggest will be here in downtown Baltimore.
Metro To Run Extra Trains For Fireworks In D.C.
Metro says it will operate extra trains during the evening of the July Fourth holiday to help passengers get to and from the National Mall for the fireworks display.
Leave It To The Pros: Fire Officials Discourage Consumer Fireworks
We are less than a week away from Fourth of July celebrations and for many people that means fireworks. But beware: state officials say fireworks caused nearly $1.5 million in damages last year.
Fireworks Blamed For Overnight Blaze That Damaged Annapolis Home
Firefighters say legal fireworks left in a trash in the garage of an Annapolis home caused an estimated$250,000 in damages.
Best Firework Displays Across the Country
From the patriotic heart of Washington, D.C. to the big city flash of New York, these spots are known for their impressive summer events.
Best Places To See Fireworks In Baltimore
The best festivals and fairs cap off the night with colorful fireworks displays. Read on for a list of some great ones to enjoy this summer.
Best 4th Of July Parties In Baltimore
This year, choose a 4th of July party destination that fits everyone's interests.


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Shoeless Joe Jackson
Babe Ruth World Series watch auctioned for $717K, Shoeless Joe's bat for $956K
Babe Ruth's pocket watch from the 1923 World Series has sold for $717,000 at auction in New York City. A 1911 game-used bat from "Shoeless" Joe Jackson sold for $956,000.
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6th May 2015
Nigel Farage pulls out of answering questions from PinkNews readers 51
5:30 PM — UKIP leader Nigel Farage has pulled out of answering PinkNews readers' questions, despite agreeing to take part in a Q&A ahead of tomorrow's general election.
Q&A: Nicola Sturgeon on Gender X passports, 'conversion' therapy and gay blood bans 8
10:22 AM — Scottish First Minister Nicola Sturgeon has addressed a number of LGBT issues including gay blood bans, the recognition of people who do not identify as male or female, and 'gay cure' therapies.
1st May 2015
Q&A: Natalie Bennett on polyamory, Gender X passports and 'gay cure' therapy 1
2:09 PM — Green Party leader Natalie Bennett has made commitments to introducing Gender X passports, ending the gay blood donation ban, and said she is "open" to legal recognition for relationships between more than two people.
29th April 2015
David Cameron attacked by Christians for pledge to end gay 'cure' therapies 84
1:28 PM — David Cameron has been condemned by a Christian group for a pledge to end "profoundly wrong" gay 'cure' therapies.
Submit your questions for Plaid Cymru leader Leanne Wood's PinkNews readers' Q&A
11:15 AM — Ahead of next month's general election, Plaid Cymru leader Leanne Wood has agreed to answer PinkNews readers' questions in a Q&A.
27th April 2015
Ed Miliband: I would still love my children 'unconditionally' if they were transgender 2
7:42 PM — Labour leader Ed Miliband has told PinkNews that he would "do his best" to support his children, if either of them came out as transgender.
21st April 2015
Submit your questions here for Nicola Sturgeon's PinkNews readers' Q&A
1:36 PM — Ahead of next month's general election, SNP leader and Scottish First Minister Nicola Sturgeon has agreed to answer PinkNews readers' questions in a Q&A.
2nd April 2015
Submit your questions for Ed Miliband's PinkNews readers' Q&A
1:27 PM — Ahead of May's election, Labour leader Ed Miliband has agreed to answer questions submitted by PinkNews readers.
23rd March 2015
Submit your questions for Natalie Bennett's PinkNews readers' Q&A
12:08 PM — Green Party leader Natalie Bennett has offered to answer readers' questions in a Q&A with PinkNews readers – and here lies your chance to submit a question.
11th March 2015
Submit your questions for David Cameron's PinkNews readers' Q&A
10:50 AM — Prime Minister David Cameron has agreed to take part in a Q&A with PinkNews readers - and here lies your chance to submit a question.
24th January 2015
Q&A: Stonewall CEO Ruth Hunt answers readers' questions 84
8:00 PM — Stonewall CEO Ruth Hunt has answered a series of questions posed by PinkNews readers.
14th October 2014
Australia: TV station defends live transphobic tweets as 'appropriate for broadcast' 5
3:42 PM — An Australian television station has defended itself from backlash after it aired transphobic tweets on a Q&A panel show.
18th March 2014
Nigel Farage confirms that UKIP will not campaign to abolish same-sex marriage 58
12:26 PM — In January, we invited PinkNews readers to submit their questions to UKIP leader Nigel Farage. The overwhelming subject mentioned was whether he would get rid of existing same-sex marriages.
20th January 2014
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Isvara Organics Coconut Sun Screen SPF 30 -- 5.5 fl oz
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Protect and nourish your skin with unrefined coconut oil and shea butter. Formulated to moisturize and give you the healthy glow of youth.
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ZEV Technologies Race Connector Glock All Models 2 lb
- Information
The ZEV Technologies V4 Race Connector is laser cut from proprietary stainless steel, tempered and mirror polished. The improved connector surface geometry provides for the lightest, most crisp trigger pull possible while still maintaining a positive trigger reset. When used with the ZEV Technologies Competition Spring Kit (246-023), trigger pull weight is reduced down to 2 lbs total. Fits all Glock models.
Delivery Information
The total weight of the product, including the product's packaging as it sits on our shelf. Since some products ship directly from the Manufacturer, their weight may be unavailable. Because of variations in the manufacturing process, similar products may have differing weights. Unless the product is designated as "Ships Alone", Shipping Weight does not include the shipping box or packing materials associated with your order.
Product ships from MidwayUSA, separate from any other products on your order due to its size. Products that are Shipped Alone incur separate "Per Order" and "Per Pound" shipping charges.
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