Head & Neck Cancer

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.

The recent recognition that theaddition of concurrent chemotherapyto definitive radiationcan improve locoregional control, organpreservation, and survival in patientswith squamous cell head andneck cancer has had a significant impacton our management choices.Chemoradiotherapy data from metaanalyses,cooperative group trials, andlarge tertiary care institutions now suggestthat there is a realistic potentialfor cure in almost all patients withlocoregionally confined disease, and thefocus has increasingly shifted towardthe impact of our treatments on longtermfunction. In the past, control ofneck node involvement often requireda comprehensive neck dissection, a procedureassociated with some degree oflong-term morbidity. In this review,Kutler, Patel, and Shah address the importantquestion of whether the neckdissection should be a planned componentin the management of patientstreated with definitive concurrentchemoradiotherapy.

COPENHAGEN, Denmark-Radiation in 6 fractions per week is significantly better than the same dose given on a more leisurely 5-fractions-per-week schedule for treating squamous-cell head and neck cancer, according to investigators from the Danish Head and Neck Cancer Study Group (DAHANCA).

Oropharyngeal mucositis hasbeen reported as the mostbothersome side effect by patientsundergoing myeloablative regimens,and it remains a therapy-limitingtoxicity of radiation and chemotherapyfor head and neck cancer. JoelEpstein and Mark Schubert providean informative review of progressmade over more than a decade of researchon the pathophysiology andmanagement of oropharyngeal mucositisin patients undergoing cancertreatment.

Rash is a class effect of HER1/epidermal growth factor receptor(EGFR)-targeted agents, and has occurred with high frequency and ina dose-dependent manner in clinical trials of these agents in cancerpatients. Analysis of phase II trials of erlotinib (Tarceva) in non–smallcelllung cancer, head and neck cancer, and ovarian cancer shows asignificant association between rash severity and objective tumor response.Rash severity was highly significantly associated with survivalin patients with non–small-cell lung cancer receiving erlotinib; mediansurvival in patients with no rash was 46.5 days, compared with257 days in those with grade 1 rash (P < .0001) and 597 days in thosewith grade 2/3 rash (P < .0001). Similarly, for the combined non–smallcelllung cancer, head and neck cancer, and ovarian cancer studies,median survival in patients with no rash was 103 days, compared with191 days in those with grade 1 rash (P = .0001) and 266 days in thosewith grade 2/3/4 rash (P = .0001). Similar findings have been madewith cetuximab (Erbitux) and in some settings with gefitinib (Iressa).The strong association of rash severity with response/survival suggeststhat rash may serve as a marker of response to erlotinib treatment andmay be used to guide treatment to obtain optimal response. Dosingerlotinib at the maximum tolerated dose, which is associated with morefrequent and more severe rash, may improve response rates and survivaldurations. Further study of the potentially important associationbetween rash and outcome of treatment with EGFR-targeted agents isneeded.

Paragangliomas are unusual tumorsof the head and neck butshould be included in the differentialdiagnosis of lateral neck masses.Although malignant paragangliomasare possible, these tumors are usuallybenign. Nevertheless, treatment canlead to great morbidity and possiblemortality. The article by Drs. Hu andPersky addresses a multidisciplinaryapproach to these lesions.

Paragangliomas most commonly occur in the carotid body, jugulotympanicarea, and vagus nerve but have also been reported in otherareas of the head and neck. These tumors are highly vascular andcharacteristically have early blood vessel and neural involvement,making their treatment particularly challenging. Surgery has traditionallybeen the preferred method of treatment, especially in light of recentadvances in technique. However, compared to radiation therapy, it canresult in a higher incidence of cranial nerve dysfunction. Radiationtherapy has the advantage of avoiding the increased morbidity ofsurgery while offering an equal possibility of cure. Part 2 of this articlediscusses radiation therapy as primary treatment of patients who areineligible for surgery and the elderly and infirm. Results with radiotherapyare comparable to those achieved with surgery. The efficacy ofsalvage therapy with either surgery or radiation is discussed, and atreatment algorithm for these tumors is proposed.

We have reviewed with interestthe article by Drs. Huand Persky and would liketo congratulate them on an excellentand comprehensive overview of theevaluation and management ofparagangliomas of the head and neck.Their review begins with an excellentlydetailed description of thedisease and staging work-up. Withmodern imaging, most paragangliomasare convincingly diagnosed basedon typical location (carotid bifurcation,nodose ganglia of the vagusnerve, middle ear along tympanic plexus,or near jugular bulb) and characteristicradiographic appearance(hypervascular, intensely enhancingmass). A tissue diagnosis is usuallyunnecessary for such lesions.

Paragangliomas most commonly occur in the carotid body, jugulotympanicarea, and vagus nerve but have also been reported in otherareas of the head and neck. These tumors are highly vascular andcharacteristically have early blood vessel and neural involvement,making their treatment particularly challenging. Surgery has traditionallybeen the preferred method of treatment, especially in light of recentadvances in technique. However, compared to radiation therapy, it canresult in a higher incidence of cranial nerve dysfunction. Radiationtherapy has the advantage of avoiding the increased morbidity ofsurgery while offering an equal possibility of cure. Part 1 of this two-partarticle focuses on techniques for diagnosing paraganglioma and theindications for and use of surgery as primary treatment. The complicationscommonly associated with surgery are reviewed, and strategies forrehabilitation of affected patients are presented.

Part of the multidisciplinary approach to cancer care involves surgical intervention. This is harmoniously interwoven through the efforts of the surgical oncologist and the reconstructive surgeon. As elegantly pointed out by Drs. Hasen, Few, and Fine, the reconstructive surgeon’s role in the management of malignancy is critical, involving the restoration of form and function. Sometimes, as in breast reconstruction, quality of life is improved by the restoration of form; other times, as in head and neck reconstruction, it is improved by the restoration of form and function. In fact, due to the significant morbidity associated with major ablation of head and neck cancer, such radical surgery would not be feasible without concomitant reconstruction.

Quon and Harrison have performed a considerable service to patients with head and neck cancers by reminding the oncology community that a state-of-the-art treatment team must include state-of-the-art brachytherapy