Head & 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.

Head and neck cancers are a diverse group of diseases, each with its own distinct epidemiologic, anatomic, and pathologic features, natural history, and treatment considerations. Despite improvements in diagnosis and local management, long-term survival rates for patients with this disease have not increased significantly over the past 30 years and are among the lowest for the major cancers.

Combined-modality positronemissiontomography (PET)–computed tomography (CT) isbecoming the imaging method ofchoice for an increasing number ofoncology indications. The goal of thispaper is to review the evidence-basedliterature justifying PET-CT fusion.The best evidence comes from prospectivestudies of integrated PETCTscans compared to other methodsof acquiring images, with histopathologicconfirmation of disease presenceor absence. Unfortunately, veryfew studies provide this kind of data.Retrospective studies with similarcomparisons can be used to provideevidence favoring the use of integratedPET-CT scans in specific clinicalsituations. Also, inferential conclusionscan be drawn from studies whereclinical rather than pathologic dataare used to establish disease presenceor absence.

Dr. Colasanto and his associatesare to be commended forskillfully and comprehensivelyreviewing the issues concerning theprovision of nutritional support to patientsundergoing radiation therapy.Their recommendations are well supportedby review of scientific studies,and the article is written in such a wayas to be accessible to those not fullyversed in prescribing nutritional support.There remain a few points thatdeserve discussion.

What do we know for sureabout the health implicationsof inappropriateweight and nutrition? We know thatapproximately 60% of US adults currentlyare considered overweight orobese[1] and approximately 300,000deaths a year in this country are associatedwith overweight and obesity.And, most importantly for this discussion,we know that randomizedcontrolled trials suggest that lifestylechanges resulting in the loss of excessweight reduce the risk cardiovasculardisease, lower blood pressure, lowerblood sugar, and improve lipid levels.[2] In essence, there is a chain ofevidence: A medical condition exists,the condition causes adverse outcomes,with interventions the conditioncan be reversed, and the problemsit causes can be ameliorated.

Malnutrition plays a key role in the morbidity of head and neckcancer patients receiving surgery, chemotherapy, radiotherapy, or combined-modality therapy. In addition to weight lost prior to the diagnosisof head and neck cancer, the patient may lose an additional 10% ofpretherapy body weight during radiotherapy or combined-modality treatment.A reduction of greater than 20% of total body weight results inan increase in toxicity and mortality. Severe toxicity can result in prolongedtreatment time, which has been implicated in poor clinical outcome.Early intervention with nutritional supplementation can reducethe chance of inferior outcome in patients at high risk of weight loss.The preferred route of nutritional support for these patients is enteralnutrition. Two commonly used methods for enteral feedings arenasoenteric and percutaneous endoscopic gastrostomy. It is importantto take into account the ethical considerations involved in providinglong-term nutritional support, particularly for patients with terminalconditions. Nutritional directives are best evaluated throughmultidisciplinary efforts, including input from the patient as well asmembers of the nursing, nutritionist, and medical staff.

Perhaps no other group of malignanciesis more severely affectedby the problems patients havewith establishing or maintaining goodnutrition than those of the upper aerodigestivetract. Nutrition, or malnutrition,is a critical considerationduring all phases of the diagnosis, treatment,and long-term management ofpatients with head and neck malignancies, even following curative therapy.

In their article, Rusthoven and colleagueshighlight the utility ofcombined positron-emission tomography/computed tomography(PET-CT) imaging for diagnosing primaryand recurrent head and neckcarcinoma, and for defining tumor targetvolumes for radiotherapy treatmentplanning in the head and neck. PEToffers noninvasive measures of tumorbiology yet suffers from limited spatialresolution; the physiologic informationobtained with PET is complementaryto the high-resolution structural informationobtained with CT or magneticresonance imaging (MRI).

Positron-emission tomography(PET) and computed tomography(CT) fusion imaging is arapidly evolving technique that is usefulin the staging of non–small-celllung cancer (NSCLC), Hodgkin’s disease,ovarian cancer, gastrointestinalstromal tumors, gynecologic malignancies,colorectal malignancies,and breast cancer. In their article,Rusthoven et al[1] describe the roleof PET-CT in head and neck malignanciesand include a review of allcurrently available literature. Accordingto the authors, PET-CT is usefulfor staging head and neck carcinomasand for target volume delineation duringradiation treatment planning.

The fusion of 18-fluorodeoxyglucose (FDG) positron-emission tomography(PET) with computed tomography (CT) offers both anatomicand physiologic delineation of head and neck cancers. PET-CT is usefulin the staging of head and neck carcinomas and may identify unsuspecteddistant metastasis that may alter treatment. PET-CT may alsohelp in target volume delineation during radiotherapy (RT) treatmentplanning. Better characterization of the target may improve local controlas well as spare normal tissues from RT sequelae.

In 2005, it is estimated that head and neck cancers will comprise 2%-3% of allcancers in the United States and account for 1%-2% of all cancer deaths. Thistotal includes 20,780 cases of oral cavity cancer, 9,880 cases of laryngeal cancer,and 8,590 cases of pharyngeal cancer. Most patients with head and neckcancer have metastatic disease at the time of diagnosis (regional nodal involvementin 43% and distant metastasis in 10%).

The past several years have seenthe fruition of a new era in cancertherapy-targeted approachesusing biologic modifiers.However, as the clinical experiencewith novel inhibitors grows, some ofthe premises on which the treatmentswere designed are being challenged,and clinical findings are leading to newparadigms. Drs. Song and Raben providea forward-thinking review of thestatus of epidermal growth factor receptor(EGFR)-targeted therapy in headand neck cancer, a paper that serves toboth highlight progress and raise issuesthat continue to challenge the implementationof targeted therapy.

The treatment of head and neck cancer has been at the forefront ofnovel therapeutic paradigms. The introduction of drugs that interactwith selective biologic pathways in the cancer cell has generated considerableattention recently. A wide variety of new compounds that attemptto target growth-signaling pathways have been introduced intothe clinic. A majority of studies in the clinic have focused on epidermalgrowth factor receptor (EGFR) antagonists, but future studies will likelybuild upon or complement this strategy with agents that target angiogenicor cell-cycle pathways. EGFR activation promotes a multitude ofimportant signaling pathways associated with cancer development andprogression, and importantly, resistance to radiation. Since radiationtherapy plays an integral role in managing head and neck squamouscell cancer (HNSCC), inhibiting the EGFR pathway might improveour efforts at cancer cure. The challenge now is to understand whenthe application of these EGFR inhibitors is relevant to an individualpatient and how or when these drugs should be combined with radiationor chemotherapy. Are there molecular markers available to determinewho will respond to EGFR inhibitors and who should be treatedwith alternative approaches? What are the mechanisms behind intrinsicor acquired resistance to targeted agents, and how do we preventthis problem? We need to formulate integrated laboratory/clinicalresearch programs that address these important issues.

Head and neck squamous cellcarcinoma (HNSCC) is themost common malignant neoplasmarising in the upper aerodigestivetract, accounting for approximately40,000 new cases each yearin the United States. Despite increasingawareness of the importance ofearly cancer detection, the majorityof patients continue to present withadvanced-stage (stage III/IV) disease.Standard therapy has included surgicalresection followed by externalbeamradiation or chemotherapy inconjunction with radiotherapy(chemoradiation). Although no prospectiveclinical trials have comparedsurgical with nonsurgical therapies,only 50% of patients are cured of theirprimary tumors. Even with successfuleradication of the primary tumor,second primary tumors can be expectedto occur at the rate of 4% to 5% peryear and are often fatal. Given the extrememorbidity and mortality ofHNSCC, new and innovative treatmentsbased on the biologic alterations thatcharacterize these tumors are required.

NEW ORLEANS-Cetuximab (Erbitux) plus high-dose radiation therapy (RT) significantly improved survival in patients with advanced head and neck cancer, compared with RT alone, according to results of an international phase III trial reported at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 5507).

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

In this issue of ONCOLOGY, Kutleret al eloquently address the concept,application, and controversiesof a planned neck dissection inpatients with head and neck carcinomaand nodal metastasis who receivenonsurgical therapy to the primary tumor.As stated lucidly in the article,planned neck dissection arose in thehistorical context of low rates of completeresponse in patients with N2/3neck disease treated with conventionallyfractionated radiotherapy, coupledwith low surgical salvage ratesamong patients who failed in the neck.Hence, the concept evolved that allpatients with N2/3 neck disease shouldundergo a planned neck dissection regardlessof response to radiotherapy.

The presence of regional nodal metastases represents a significantadverse prognostic factor for patients with squamous cell carcinoma ofthe head and neck. Early-stage head and neck cancers, localized to theprimary site without regional lymph node metastases have excellentcure rates with either surgery or radiation therapy. The presence ofregional metastases results in cure rates that are approximately half ofthose obtainable in early-stage disease. Therefore, due to the significantadverse impact of neck metastases on prognosis, the treatment ofthe neck remains a vital part of the decision-making process in determiningtherapy for head and neck cancer.