Head & Neck Cancer

In its second annual "Clinical Cancer Advances" report, the American Society of Clinical Oncology (ASCO) selected six notable developments in clinical cancer research as most important in 2006.

In RTOG 9111, a randomized phase III trial in locally advanced laryngeal cancer, there was no difference in overall survival between the three arms, but disease-free survival, locoregional control, and preservation of the larynx were better in patients receiving induction chemotherapy plus radiation or concurrent chemoradiation, compared with radiation therapy alone.

A device that displays a holograph-like 3-dimensional (3D) image, created from a CT, MRI, or PET dataset, holds promise for more accurate radiotherapy treatment planning (see image on page 1). James C. H. Chu, PhD, professor of radiation oncology, Rush University Medical Center, presented results of a pilot study of the Perspecta Spatial 3D System, developed by Actuality Systems, Inc. (Bedford, Massachusetts), at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology

The FDA has approved Taxotere (docetaxelfor injection, Sanofi-Aventis), in combinationwith cisplatin and fluorouracil andadministered prior to radiotherapy, forthe treatment of patients with inoperable,locally advanced squamous cell carcinomaof the head and neck (SCCHN).

The science supporting molecularly targeted therapies for the treatment of patients with solid tumors continues to evolve. Nurses are challenged to understand cell signaling, molecular targeting, and the mechanism of action of targeted agents. Two cell signal transduction pathways regulate the development, proliferation, and metastasis of solid tumors: the human epidermal growth factor (HER) receptor pathway and the vascular endothelial growth factor (VEGF) receptor pathway. Several novel pharmacologic agents with distinct indications and methods of administration target the HER and VEGF molecular pathways.

A systematic approach to early treatment of skin toxicity in patients on erlotinib (Tarceva)-based therapy can reduce the need for dose modification or delay in patients with head and neck cancer or non-small-cell lung cancer (NSCLC)

Cetuximab (Erbitux), a chimeric antiepidermal growth factor receptor monoclonal antibody currently used to treat metastatic colorectal cancer, is in clinical development for several other solid tumors. Although cutaneous manifestations are the most common toxicities associated with cetuximab, they are rarely life-threatening. Cetuximab-related infusion reactions are less common, but they may become severe and cause fatal outcomes if not managed appropriately. Little about the specific etiology of these events is known; however, an overview of infusion reactions observed with other compounds may shed some light and help characterize cetuximab-related reactions. For physicians administering cetuximab, familiarity with acute reaction treatment protocols and preparedness to identify and manage symptoms promptly and effectively are most important to minimize potential risks.

Jeff is a 47-year-old white male who presented to his primary care provider complaining of having had swollen lymph nodes in the right neck for 2 months. He also complained of nasal stuffiness and sore throat. Physical exam found lymphadenopathy in the left cervical triangle less than 2 cm in diameter. He smokes about 2 packs of cigarettes a day and has a 60 pack-year history of smoking. He has been a cabinet-maker for almost 20 years. He has no other significant medical history and is not on any regular medications. He is a social drinker and denies any illicit drug use. He was treated with an antibiotic for 10 days, but on return the lymphadenopathy appeared slightly enlarged. He was sent to an ear, nose, and throat specialist who biopsied the nodal mass. Following an extensive workup, he was diagnosed with stage III (T2, N1, M0) squamous cell carcinoma of the nasopharynx.

There is sufficient evidence to show that asbestos exposure can cause cancer of the larynx.

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past few years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate therapy but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. The condition involves exposed bone of the maxilla or mandible. Although it is often associated with a recent dental surgical procedure, spontaneous ONJ can also occur. Patients commonly present with symptoms. Through case reporting and clinical experience, there is a suggestion that the incidence of ONJ in patients with cancer receiving intravenous bisphosphonates ranges between 1% and 10%. Management of ONJ focuses on maximizing oral health, conservative actions with mouth rinses, antibiotics, and avoidance of unnecessary invasive dental procedures. The currently available data on ONJ are reviewed here.

The TPF induction regimen-docetaxel (Taxotere), cisplatin, fluorouracil (5-FU)—followed by carboplatin-based chemoradiotherapy (CRT) is a "new acceptable standard of care" for locally advanced squamous cell carcinoma of the head and neck (SCCHN

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms.

Since initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.

The FDA has approved the marketing of the first new drug for the treatment of head and neck cancer in nearly half a century and granted it two indications.

ImClone Systems Incorporated and Bristol-Myers Squibb Company recently announced that the US Food and Drug Administration (FDA) has approved cetuximab (Erbitux), an immunoglobulin (Ig)G1 monoclonal antibody, for use in the treatment of squamous cell carcinoma of the head and neck.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

PHOENIX-Zila, Inc. has enrolled the first patients in its phase III clinical trial of OraTest, a rinse for detecting severe dysplasia and cancer in patients at elevated risk for oral cancer. Its active ingredient is Zila Tolonium Chloride (pharmaceutical grade toluidine blue). The trial is expected to require fewer than 4,000 high-risk patients, generally requiring a single visit; it will be conducted at approximately 13 investigative sites.

The epidermal growth factor receptor (EGFR) promotes the growth of different cell types and has been implicated in tumorigenesis. The EGFR comprises a family of four structurally similar tyrosine kinases with a complex link to downstream signaling molecules that ultimately regulate key cell processes. Anti-EGFR agents have been developed as promising therapeutic anticancer targets, and some have been recently approved for the treatment of non-small-cell lung cancer and colon cancer. The two anti-EGFR therapies with the greatest clinical application are monoclonal antibodies that block the binding of ligands to EGFR and small-molecule tyrosine kinase inhibitors that inhibit the binding of adenosine triphosphate to the internal tyrosine kinase receptor of EGFR. We attempt to give an overview of the EGFR function and biology, focusing on the most important clinical findings and applications of EGFR inhibitors in lung and head and neck cancer.

PHILADELPHIA-In a phase III randomized trial, the addition of cetuximab (Erbitux) to standard radiotherapy resulted in improved locoregional disease control and enhanced survival in patients with advanced squamous cell carcinoma of the head and neck, according to a poster presentation (poster B106) at the annual AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

In 2005, an estimated 29,370 newcases of oral cavity and pharyngealcancers were diagnosed inthe United States, accounting for2.14% of all cancer cases.[1] Over7,000 individuals will die from thesecancers in this country in 2005-approximately one death per hour.Many advances have been made inthe diagnosis and treatment of thesecancers, yet the mortality rate remainshigh (5-year survival rate of ~50%).Probably the most important approachis early detection, since early-stagetumors are associated with markedlybetter survival rates than late-stagecancers that have already spread toregional tissues and lymphatics.

Xerostomia is a permanent and devastating sequela of head and neckirradiation, and its consequences are numerous. Pharmaceutical therapyattempts to preserve or salvage salivary gland function through systemicadministration of various protective compounds, most commonlyamifostine (Ethyol) or pilocarpine. When these agents are ineffective orthe side effects too bothersome, patients often resort to palliative care, forexample, with tap water, saline, bicarbonate solutions, mouthwashes, orsaliva substitutes. A promising surgical option is the Seikaly-Jha procedure,a method of preserving a single submandibular gland by surgicallytransferring it to the submental space before radiotherapy. Improved radiationtechniques, including intensity-modulated radiotherapy andtomotherapy, allow more selective delivery of radiation to defined targetsin the head and neck, preserving normal tissue and the salivary glands.Acupuncture may be another option for patients with xerostomia. All ofthese therapies need to be further studied to establish the most effectiveprotocol to present to patients before radiotherapy has begun.

The review by Kahn andJohnstone published in this issueof ONCOLOGY is comprehensiveand interesting. A fewpoints deserve emphasis, the first ofwhich is the issue of how we shouldmeasure and report xerostomia. Accurateand reliable measurements ofxerostomia are necessary in order toproperly assess its severity, timecourse, dose-response relationships,and the efficacy of measures to protectthe glands or to stimulate salivaryproduction following irradiation. Xerostomiaencompasses the objectivereduction in salivary output andchanges in its composition, as well asthe subjective symptoms reported bythe patient. Currently available measurementsof xerostomia include(1) functional imaging of gland activity,(2) measurements of the salivaryoutput, (3) observer-assessed toxicitygrading, and (4) instruments assessingpatient-reported evaluation of thevarious xerostomia-related symptoms.

This supplement to Oncology News International includes more than 15 reportson presentations made at the 41st annual meeting of the American Society of Clinical Oncology.Reviews focus on the use of targeted agents in non–small-cell lung cancer and other solid tumors,evaluating the novel therapies bevacizumab, cetuximab, bortezomib, erlotinib, and gefitinib, aloneand/or in combination with other chemotherapy agents. Continuing medical education credit isavailable by completing a post-test and evaluation online at www.cancernetwork.com/cme.

Anaheim, California-A large case-controlled Norwegian health service cohort study found that regular NSAID (Anaheim, California-A large case-controlled Norwegian health service cohort study found that regular NSAID (nonsteroidal anti-inflammatory drug) use of 5 years or more cut oral cancer risk in half among heavy smokers, but also doubled their risk of cardiovascular (CV) death. Notably, while the study investigated nonselective NSAIDs, it did not assess COX-2 inhibitors.

Argiris et al present a comprehensivereview of inductionchemotherapy for head andneck cancer, and should be lauded fortheir meticulous work. This papercarefully delineates and categorizesmost of the relevant induction chemotherapystudies in head and neckcancer performed over the past 3 decades.The authors have sought to answerquestions regarding the optimalnumber of chemotherapy cycles (acritical factor when one uses responseto induction chemotherapy to determineeligibility for organ preservationor in an attempt to enhance curerates), the optimal chemotherapyregimen, and the possibility of a sitespecificbenefit to induction chemotherapy.The paper assesses benefitbased on treatment intent-that is, organpreservation vs survival benefit.Importantly, by excavating the layersof the past, the authors provide aframework with which to construct anew paradigm of treatment for headand neck cancer that may again incorporateinduction chemotherapy.

Argiris and colleagues presenta comprehensive review of25 years of phase II/III trialsusing multimodality therapy for locallyadvanced head and neck squamouscell cancer (HNSCC). Theyfocus on two approaches: inductionchemotherapy followed by definitivelocal therapy (surgery and/or radiotherapy)and concurrent chemoradiotherapy.In sorting through thesetrials, the authors review the controversiesin the management of locallyadvanced HNSCC, while also presentinga rationale for a unified approach-combining induction andconcomitant chemoradiotherapy in amultimodality treatment paradigm.Evidence from several recent studiessuggests that this strategy will benefita subset of patients with locally advanceddisease. The stage is set forthe reevaluation of the benefit of inductionchemotherapy prior to definitivechemoradiation. To that end, threedifferent prospective phase III trialsare under way in the United States.

Argiris and colleagues report asystematic review evaluatingthe activity and potential roleof induction chemotherapy in patientswith previously untreated, locoregionallyadvanced squamous cell head andneck cancer.[1] They consider bothphase II and III published trials. Thedata reviewed in their paper, and theirthoughtful synthesis and interpretationof these data, highlight certain themes:

Squamous cell carcinomas of the head and neck are highly responsiveto induction chemotherapy. However, randomized trials have failedto demonstrate a survival advantage with the addition of induction chemotherapyto locoregional therapy consisting of surgery and/or radiationtherapy. Currently, concomitant radiation and chemotherapy hasemerged as a standard and has optimized locoregional control in headand neck cancer. In this setting, the addition of induction chemotherapymay further improve outcome by enhancing both locoregional and distantcontrol. As interest in induction regimens is renewed, we elected toconduct a systematic review of trials of induction chemotherapy forlocoregionally advanced head and neck cancer. The most studied combination-cisplatin plus fluorouracil (5-FU)-achieves objective responserates of about 80%. In a meta-analysis, induction with platinum/5-FU resulted in a small survival advantage over locoregionaltherapy alone. The introduction of a taxane into induction chemotherapyregimens has produced promising results. Induction chemotherapyshould be the subject of further clinical research in head andneck cancer. Randomized clinical trials in which the control arm isconcurrent chemoradiotherapy and the experimental arm is inductionchemotherapy followed by concurrent chemoradiotherapy are planned.Platinum/taxane combinations are the preferred regimens for furtherstudy in the induction setting and a suitable platform with which toinvestigate the addition of novel targeted agents.