Combined Chemotherapy and Radiation Therapy forHead and Neck MalignanciesQuality of Life Issues

Nam P. Nguyen, M.D.1

Sabah Sallah, M.D.2

Ulf Karlsson, M.D., Ph.D.3

John E. Antoine, M.D.1

1 Department of Radiation Oncology, University ofTexas Southwestern Medical Center at Dallas, Dal-las, Texas.

2 Division of Hematology/Oncology, University ofTennessee, Memphis, Tennessee.

3 Department of Radiation Oncology, East CarolinaUniversity, Greenville, North Carolina.

The authors thank Brenda M. Lewis and Dr. BengHuey Jo for their efforts in the preparation of thisarticle.

Address for reprints: Nam P. Nguyen, M.D., De-partment of Radiation Oncology, University ofTexas Southwestern Medical Center at Dallas, VANorth Texas Health Care System, 4500 S. Lan-caster Road, Dallas, TX 75216; Fax: (214) 857-0145; E-mail: NamPhong.Nguyen@med.va.gov

Received June 14, 2001; accepted October 11,2001.

BACKGROUND. The standard of care for locally advanced head and neck carcinoma

usually has been surgery followed by radiation therapy. Patient survival using this

approach has been reported to be poor. The disfiguration resulting from surgery

and the long-term morbidity of postoperative radiation often results in consider-

able distress. Concurrent chemotherapy and radiation was introduced to improve

outcome. Excellent local control and survival results often have been reported in

Phase II and Phase III studies. The acute toxicity of combined chemotherapy and

radiation is significant. However, organ preservation may improve quality of life.

This review article summarizes the findings from published series of surgery,

postoperative radiation, radiation therapy alone, and chemoradiation with regard

to quality of life issues for patients with locally advanced head and neck carcinoma.

METHODS. A literature search was used to identify quality-of-life studies of post-

operative radiation, radiation therapy alone, and chemoradiation in patients with

locally advanced head and neck carcinoma. Factors affecting long-term quality-

of-life issues in each treatment modality were identified, compared, and evaluated.

RESULTS. Speech disorder, dysphagia, pain, and depression were found to be the

common side effects affecting quality of life regardless of the treatment modality.

Xerostomia is the major complication affecting patients undergoing radiation or

chemoradiation.

CONCLUSIONS. Acute side effects of combined chemotherapy and radiation therapy

usually were found to resolve after treatment. Long-term morbidity is substantial

because of xerostomia and severe dysphagia. However, preliminary studies suggest

that because of organ preservation, patients may achieve a better quality of life

after chemoradiation compared with the conventional use of surgery and postop-

erative radiation. Cancer 2002;94:1131– 41. © 2002 American Cancer Society.

DOI 10.1002/cncr.10257

KEYWORDS: Chemoradiation, advanced head and neck carcinoma, quality of life,survival.

Locally advanced head and neck carcinoma carries a poor progno-sis.1 The 5-year survival usually is �40% with a combination of

surgery followed by postoperative radiation.2 Because of the extent ofthe disease, surgical resection may require removal of a large volumeof tissue. A surgical flap may be needed to fill the tissue defect andrestore organ function.3 After extensive surgery, patients usually de-velop speech and swallowing dysfunction.4,5 The severity of thespeech and swallowing disorders depends on the site of the primarytumor, the stage of the disease, the type of surgical resection used,and the quality of the graft.6 Patients also may develop residual painand body image alteration secondary to nerve damage and disfigura-

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© 2002 American Cancer Society

tion, respectively.7,8 If postoperative radiation is re-quired because of the advanced stage of the disease,further alteration of the patient’s quality of life (QOL)may occur because of the xerostomia and fibrosisinduced by radiation.9

The concept of concurrent chemotherapy and ra-diation was introduced in an attempt to improve thelocal control and possibly influence the survival be-cause of the high rate of local and distant failuresobserved with the combination of surgery and post-operative radiation.10 Many Phase II studies reporteda high local control rate and improved survival withchemoradiation in patients with inoperable head andneck disease.11–13 Long-term survival ranging from 52–76% at 4 –5 years was reported in these trials. Random-ized Phase III studies comparing concurrent chemo-therapy and radiation with radiation therapy alonealso reported a statistically significantly improved sur-vival rate for the combined modalities. The survivalrates ranged from 42–74% and 9 –52% for chemoradia-tion and radiation, respectively.14 –17 Acute toxicity ofthe combined treatment can be severe and may resultin patient death.11

However, patients who undergo chemoradiationmay not require surgery if a complete response isobtained after treatment. Organ-sparing surgery alsomay be possible for a residual neck or tumor massafter its shrinkage. Therefore, QOL may be improvedafter chemotherapy and radiation.

Conversely, long-term sequelae may be due to theenhanced radiosensitization effects of chemotherapy.Late complications were observed in 7.5–20% of pa-tients undergoing chemoradiation for locally ad-vanced head and neck carcinoma.18 Excessive fibrosisand xerostomia may have a negative impact on speechand swallowing. These factors may counterbalancethe benefit of organ preservation.

The goal of the current article was to review dataconcerning the effect of chemoradiation on QOL com-pared with the traditional approach of surgery andpostoperative radiation for patients with locally ad-vanced head and neck carcinoma.

DefinitionQOL is defined broadly as a person’s sense of well-being stemming from satisfaction or dissatisfactionwith areas of life that are important.19 Individualsdiffer in level of expectations. Frustrations may arisewhen the results do not match expectations.20 Giventhe definition’s complexity and lack of specificity, it isnot surprising that QOL is not an easily measuredquantity. Assessment of QOL usually is assessedthrough questionnaires.21 The questions investigatespecific items called domains that range from func-

tional to economic status affected by the disease ortreatment.

QOL QuestionnairesAll tests measuring QOL examine four basic domains:psychologic (e.g., depression, anxiety), social (e.g.,sexual interests, leisure activities), occupational (e.g.,employment, household activities), and physical (e.g.,sleep, pain).22 The questions are aimed toward deter-mining a possible causal relation (such as a correla-tion between severity of vomiting and QOL) or under-lying indicators of a patient’s personality, such asanxiety, which may influence their perception ofsymptoms (for example a depressed patient is morelikely to perceive an episode of vomiting as severelyaffecting QOL). Each item is assigned a score (simpleor weighted) and summation of the scores provide theglobal QOL. High scores for a functional scale (e.g.,social functioning) represent a healthy level. However,high scores for a symptom item such as pain indicatea higher degree of impairment.

There are four types of questionnaires that ad-dress specific issues in cancer management: global,general, head and neck, and performance. The globalquestionnaires can be applied for any disease (malig-nant or not) because the questions are directed to-ward physical, social, and psychologic issues. The gen-eral questionnaires examine cancer symptoms such asfatigue, pain, and the side effects of treatment. Headand neck questionnaires focus on specific issues re-lated to head and carcinoma treatment side effectsand complications. Performance questionnaires mayaddress specific functions such as speech or swallow-ing.

The questionnaires vary in their complexity andmay or not include psychologic issues. Commonlyused questionnaires in head and neck patients are: theEuropean Organization for Research and Treatment ofCancer Quality of Life Questionnaire Core 30 (EORTC-C30), Head and Neck Core 35 (EORTC-HN35), Univer-sity of Washington Head and Neck Disease-SpecificMeasure (UW-QOL), and Head and Neck Radiother-apy Questionnaire (HNRQ).23–25 UW-QOL is a quickway to assess disease-specific functional items such aspain, disfigurement, and swallowing.23 However, psy-chologic issues are omitted in the UW-QOL question-naires, making it best suited for a busy clinical practicebecause it is easy and simple to use.

EORTC-C30 questionnaires are more complexand include multiple functions ranging from emo-tional to social function.24 As a result, it may take moretime for patients to answer the questions; EORTC-C30questionnaires usually are employed for research pur-

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poses and are validated for a wide range of malignan-cies.

The EORTC-HN35 is used specifically for headand neck carcinoma. It contains seven symptomscales (pain, swallowing, taste, social eating, socialcontact, and sexuality) and six symptom items (teethproblems, trismus, dry mouth, sticky saliva, cough,speech, and feeling ill). Specific issues concerning ra-diation treatment, such as xerostomia, are measuredby the McMaster University Head and Neck Radio-therapy Questionnaire (HNRT).25 The questionnairesmay be used separately or in combination becausethey are complementary.26 Other types of head andneck questionnaires include the Head and Neck Sur-vey, Functional Status in Head Neck Cancer, Head andNeck Cancer Specific Quality of Life, and Quality ofLife Questionnaire.27–30

A questionnaire such as the Performance StatusScale for Head and Neck Cancer examines specific oralfunctions such as speech intelligibility and the pa-tient’s ability to eat.31

Although not specific to head and neck carci-noma, the Karnofsky Performance Index and HospitalAnxiety and Depression Scale are two global question-naires most commonly used to assess physical activityand depression, respectively, in patients with tumorsof the upper aerodigestive tract.32,33

Normal Physiology of Speech and SwallowingTo understand how head and neck malignancies andtheir treatment have an effect on the patient’s QOL, abrief review of the normal physiology of speech andswallowing is necessary.34

Speech sounds are produced when the airflowpasses through vibrating (vocal cords) and resonating(pharynx and the oral and nasal cavities) systems, andfinally through a partially or totally occluded oral cav-ity. Two types of speech sounds are produced: vowelsand consonants. Vowels are produced by the modifi-cation of size and shape of the resonant cavities. Con-sonants are produced when the airflow speed is mod-ified by various articulators (tongue, lips). The tongueacts as a major modulator in the production of vowelsor consonants because of its ability to modify the sizeand shape of the oral cavity as well as the degree ofobstruction of the vocal tract. However, any disrup-tion of the structures involved in speech productionby the tumor or its treatment will affect the voice’sintelligibility, and thus compromise a patient’s QOL.

Swallowing movement occurs through three stages:oral, pharyngeal, and esophageal. The tongue pushesthe food bolus against the hard palate during the oralstage. In the next (pharyngeal) stage, elevation of thetongue and depression of the soft palate force the

bolus into the oropharynx. Closure of the airway andpalatopharynx by the epiglottis and soft palate, re-spectively, prevents the food from being aspirated andregurgitated through the nasopharynx. In the lastphase, the esophageal phase, the bolus enters theesophagus.

Objective Evaluation of Speech and Swallowing inPatients with Head and Neck Cancer CarcinomaThere are two major methods of assessing speechfunction: articulatory and speech intelligibility testing.Articulatory testing evaluates the functions of majorarticulators such as the lips and tongue. Intelligibilitytesting examines the quality of the phonation. The twotests usually are performed before and after head andneck surgery to assess the impact of surgical treatmenton voice quality. Before surgery, dysfunction of thevoice was observed in patients with locally advancedhead and neck tumors.35 Additional speech deteriora-tion may occur after surgery.

Quality of the voice after surgery is dependent onmultiple factors: extent of surgical resection, tumorstage, tumor site, type and quality of the graft, andseverity of impairment of the tongue mobility.6,35,36

Extensive ablation of the tongue muscles is associatedwith severe reduction of speech intelligibility.37 As aresult, surgery for advanced tumors (TNM stage T3and T4) produce a higher degree of speech dysfunc-tion because of the amount of tissue resected toachieve a negative margin.35,38 Large surgical defectsusually are reconstructed after surgery to restore nor-mal functions. The method of surgical reconstructionalso has an impact on speech quality. Myocutaneousand fasciocutaneous flaps result in decreased tonguemobility compared with jejunal grafts.5 Jejunal flapsproduce better postoperative articulation because thejejunum is more pliable and may stretch extensivelybecause of the surface folds. Local grafts may producesuperior speech quality compared with other types ofgrafts.35 However, even with reconstructive surgery, asignificant decrease in tongue mobility was observedafter oral surgery for carcinoma of the floor of themouth and tongue.6,37,39 The effect on the intelligibil-ity of speech was more pronounced when the mobilityof the tongue base and dorsum was reduced.36 As aresult, surgery of the base of the tongue is associatedwith significant speech dysfunction compared withother tumor sites.38 The percentage of the soft palatethat is resected also is reported to affect speech func-tion negatively because of the decreased intraoralpressure required for the production of phonemes.Postoperative radiation does not appear to impairspeech quality despite the xerostomia produced.6,9

Swallowing motility disorders are investigated

Combined Therapy for Head and Neck Malignancies/Nguyen et al. 1133

with videofluoroscopy or videofluorography. Dyspha-gia is a common symptom of tumors of the upperaerodigestive tract. Up to 59% of patients report aswallowing problem prior to treatment.40 All threephases of swallowing may be affected by the tumor.Compared with healthy volunteers, a significantlylonger oral and pharyngeal time was observed in pa-tients with head and neck carcinoma. In addition,symptomatic or asymptomatic aspiration may bepresent.41 The degree of impairment depends on theanatomic location of the tumor. Laryngeal and hypo-pharyngeal carcinomas are severely affected com-pared with other sites.41 A significantly high percent-age of aspiration also is observed with laryngeal andhypopharyngeal tumors. Locally advanced tumors areassociated with more swallowing dysfunction com-pared with early stage tumors. Given the baseline dys-function, it is not surprising that the severity of dys-phagia may be exacerbated after treatment. All threetreatment modalities (surgery, radiation therapy, andchemotherapy) may adversely affect the swallowingmechanism.

After glossectomy and reconstruction, stasis hasbeen observed in all areas of the oropharyngealtract.42 Residue is more pronounced in the vallecula,flap, and tongue stump. Other types of surgery andreconstruction also have been reported to lead to anincrease of the bolus transit time, especially the pha-ryngeal transit time.4 Dysphagia is increased markedlyif postoperative irradiation is required.9 Postoperativeradiation patients have been reported to experience alonger oral transit phase, increased pharyngeal resi-due, and reduced cricopharyngeal opening duration.

Radiation decreases the salivary flow and in-creases postoperative edema and fibrosis of the pha-ryngeal muscles. All these effects compound surgicalcomplications Patients frequently develop swallowingdysfunction 18 –22 weeks after postoperative radia-tion.43

Patients with carcinoma of the head and neck whoare undergoing radiation therapy alone also experi-ence abnormal swallowing studies after treatment. In-creased fibrosis of the pharyngeal musculature mayinduce dysmotility of the pharyngeal wall leading topharyngeal residue.44 A reduction of the followingfunctions has been observed after head and neck ra-diation: laryngeal elevation, tongue base contact tothe posterior pharyngeal wall, and true vocal cordclosure during swallowing.9

Abnormal pharyngeal contraction was observedin 93% of patients undergoing radiation therapy fornasopharyngeal tumors. In addition, a high incidenceof silent aspiration (22%) was recorded.45 High dos-ages as well as large radiation fields to cover the base

of skull may explain the severity of swallowing abnor-malities noted after radiation therapy to the nasophar-ynx.

Chemotherapy acts as a radiosensitizer and mayenhance apoptosis induced by radiation.46 As a result,the fibrotic reaction may be more intense after che-moradiation. Reduction of movement of posteriortongue base and laryngeal elevation were observed inhead and neck carcinoma patients who were under-going chemotherapy and radiation for organ preser-vation.47 Impairment of laryngeal motion, pharyngealstasis, pyriform and vallecular residue, and aspirationare functional abnormalities that are observed withthe combined modalities. The severity of the fibrosismay lead to prolonged tube feeding; for example, 6 of9 patients who received hydroxyurea concurrentlywith radiation therapy for oral cavity and pharyngealtumors continued to require gastrotomy feeding 1year after treatment.48

Major Issues Affecting Quality of LifeAfter surgeryIt is difficult to assess the QOL after surgery because ofthe heterogeneity of tumor sites and the extent ofresection. However, a few general conclusions may bemade.

PainPain remains a significant problem, particularly afterneck dissection.7,49 Arm and shoulder pain was re-ported to be persistent in up to 26% of patients at 2years after neck surgery.7 Pain appears to have anadverse effect on the general well-being of cancersurvivors and may cause serious psychologic distress.Many factors influence the development of pain: thetype of neck dissection, the stage of the tumor, and theamount of tissue resected.

The choice of neck dissection depends on thelevel of lymph nodes affected by the tumor. Selectiveneck dissection (SND) involves resection of Level I–IIIor II–IV lymph node stations with sparing of the ster-nocleidomastoid (SCM) muscle, internal jugular vein(IJV), and spinal accessory nerve (XI). SND usually isindicated for patients with clinically negative cervicallymph nodes. The lymph nodes resected by SND arethose most likely involved from the tumor based on itslocation. Radical neck dissection (RND) entails theremoval of all Level I–V lymph nodes along with theSCM, IJV, and the XI nerve. Modified radical neckdissection (MRND) allows sparing of nerve XI eventhough Level I–V lymph nodes are resected. RND isassociated with a higher incidence of pain and shoul-der dysfunction compared with SND and MRND.50

The decrease in pain is due to the sparing of cranial

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nerve XI and accompanying sensory nerves duringsurgery. The patient’s physical condition and activityalso improve with preservation of the XI nerve.49

Neck and shoulder pain is less if Level V lymphnodes also are not resected, implying a better func-tional result after SND.49 Dissection of nerve XI (topreserve it) may cause additional pain. A similar result(better pain and improved physical activity) also isobserved with the use of supraomohyoid neck dissec-tion compared with RND and MRND.51

Resection of large tumors requires extensive sur-gery, which may lead to substantial postoperativepain. The severity of pain after surgery increases withtumor stage; patients who presented with T3 and T4lesions were found to experience more pain comparedwith those patients with early-stage disease.52

Speech disorders and dysphagiaThe ability to communicate and to swallow after sur-gery is a function of the tumor stage, the anatomic siteof the tumor, and the compounding effect of radia-tion. Advanced tumor stage at diagnosis is known tohave a deleterious effect on QOL scores. Speech, swal-lowing, and the ability to eat in public are affectedadversely for patients with resected T3 and T4 le-sions.3,38 Despite reconstructive oral/throat surgery,substantial loss of soft tissue results in dysphagia,reflux of liquid, and insomnia.

To illustrate this point further, organ-preservingsurgery, whenever feasible, is associated with a betterquality of life. For example, patients undergoing su-pracricoid partial laryngectomy (SPL) were reported tohave achieved better physical function, social func-tion, and psychologic well-being compared with thosepatients who underwent total laryngectomy.53 Pa-tients who undergo SPL appear to experience less painand less emotional distress, which may be due to theabsence of the tracheostoma. The presence of a stomaafter total laryngectomy has a negative impact on cos-mesis and social acceptability.54,55 In addition, airwayirritation associated with the stoma can result in ex-cessive coughing, sleep difficulty, and fatigue.56

Among various head and neck anatomic sites, sur-gery at the base of the tongue has a negative impact onspeech and deglutition even in patients with an early-stage tumor.38 This is not surprising given the reducedmobility of the stump, even with flap reconstruction.

Radiation therapy also impairs the QOL after sur-gery.9,30 Patients often develop significant speech im-pediments, swallowing dysfunction, and psychologicdiscomfort. The QOL deterioration is more severe forthese patients compared with patients treated withradiation therapy alone.30

Patients treated with postoperative radiation also

were reported to have worse physical symptoms com-pared with the patients who were treated with surgeryalone.57

Xerostomia and fibrosis are common after radia-tion and exacerbate the surgical complications. Be-cause the majority of patients with advanced head andneck carcinoma require postoperative radiation, theirQOL can be affected significantly by the treatmentmodality combinations.

DepressionThe head and neck region is the most prominent andvisible part of the body that is not covered by clothing.This anatomic area plays an important role in theperception of body image.

Head and neck surgery can be associated withfacial disfigurement. Speech and swallowing impair-ment after surgery also impede a patient’s abilities tocommunicate and endure public appearance. Dropkindescribed a cohort of 117 patients who were about toundergo disfigurative surgery for head and neck car-cinoma. Anticipation of mutilation secondary to facialsurgery was associated with a high level of distress. Inanother population of 75 patients who actually under-went surgery for head and neck carcinoma, alterationof body image was more likely to occur in patientswho had mild to moderate disfiguration after surgery.8

The ability to cope after surgery depends on thepreoperative coping behavior of the individual. Psy-chologic therapy can help patients with adjustmentdifficulties after surgery. Pilot studies suggest long-term improvement in QOL for patients receiving psy-chologic group therapy for head and neck carcinoma.

Psychiatric morbidity, emotional function, andglobal QOL was reported to improve in the group ofpatients receiving psychologic counseling comparedwith a control group.58 This psychologic support isimportant because some of the spouses of the patientsalso were found to suffer from depression resultingfrom the patient’s illness and therefore were unable toprovide the help needed after surgery. Both patientsand their spouses developed difficulties with work andsocial activity after the patient underwent total orpartial laryngectomy for laryngeal carcinoma.59 Table1 summarizes those studies assessing issues affectingQOL after surgery.

After radiationThe morbidity from radiation therapy increases withthe volume and dose of radiation. The irradiated tar-get volume varies depending on the primary tumorsite and the tissue volume at risk for occult metasta-ses. Therefore, treatment of the nasopharynx carriessubstantial toxicity because of the large radiation field

Combined Therapy for Head and Neck Malignancies/Nguyen et al. 1135

covering the base of skull and the lymph node drain-age. Xerostomia, trismus, and swallowing disordersfrequently are reported complications in patients withnasopharyngeal carcinoma.45 Xerostomia is the mostcommon side effect in patients undergoing radiationtherapy secondary to damage of the salivaryglands.60 – 62 Severe xerostomia significantly alters QOLscores for emotional, social, physical, and overallfunction.

Patients with early stage vocal cord carcinomahave the radiation field restricted to the glottis. As aresult, the QOL scores are reported to be highest forpatients with T1 vocal cord carcinoma compared withpatients with advanced stage laryngeal carcinoma andtumors of other sites.60 Significantly lower scores forspeech intelligibility also are reported for patients withadvanced laryngeal carcinoma.61 Pain and nutritionalso are major complications resulting in psychologicdistress.62 Baseline and long-term depression also areobserved in these patients.57 These long-term effectswere observed with conventional fractionation, hy-perfractionation, and hypofractionation radiationtherapy.63– 65

However, overall, patients undergoing radiationtherapy appear to cope and adjust well. Harrison etal.66 reported excellent functional and employmentstatus for patients who received radiation treatmentfor base of the tongue tumors. Moore et al.,67 also

observed long-term functional results for patients whowere treated with radiation for tumors of the base ofthe tongue that appeared superior to those of patientswho were treated with surgery. Speech intelligibilityand return to a normal diet were noted after 5 years.However, for patients with advanced tumors (T3 andT4), the ability to tolerate a normal diet was decreasedcompared with patients whose tumors were in theearly stages. Organ preservation with radiation ther-apy for tumors of the base of the tongue most likelyaccounted for the good results reported.

The QOL for patients receiving radiation therapymay be improved further by the addition of amifos-tine. Amifostine is a thiol compound that protectsnormal tissues against radiation through the bindingof the sulfhydryl group with hydroxyl radicals. Thehigh concentration of amifostine in the salivary glandsafter its administration often decreases the severity ofxerostomia after head and neck radiation.68 In a ran-domized study, Wasserman et al. reported an im-provement in speech, eating, sleep, and overall well-being in patients receiving amifostine.69 Both arms ofthe study received curative doses of radiation for ad-vanced head and neck carcinoma. The QOL benefitsobserved for the patients receiving amifostine weredue to the improvement of xerostomia. Table 2 sum-marizes the QOL results after radiation therapy.

TABLE 1Factors Affecting Quality of Life Issues for Patients with Locally Advanced Head and Neck Carcinoma Who Undergo Surgery

AuthorsNo. ofpatients Site

Type ofquestionnaire Type of surgery Type of issues

Schliephake et al.3 85 Floor of mouth FLI Primary surgery andreconstruction

Dysphagia, reflux of liquid,sleep disorders

Dropkin8 75 Not specified STAI Not specified DepressionTerrel et al.49 175 Larynx, oral cavity, oropharynx HNQOL

SF-36, SF-12Neck dissection with or without

nerve sparingPain

Kuntz and Weymuller50 149 Oral cavity, oropharynx, larynx,hypopharynx

UW-QOL RND, MRND, SND Pain

Rogers et al.52 48 Oral cavity, oropharynx UW-QOL Primary surgery andreconstruction

Pain

Zelefsky et al.38 29 Oral cavity, oropharynx PSS-HN Not specified Speech normalcy of dietWeinstein et al.53 56 Larynx SF-36

HNQOL, VRQOLPartial laryngectomytotal laryngectomy

Speech

De Graeff et al.57 75 Oral cavity, oropharynx EORTC-C30EORTC-HN35CES-D

Primary surgeryneck dissection

Physical functioningdepression

Herranz and Gavilan59 111 Larynx PAIS-SRMCPLQ

Total laryngectomysupraglottic laryngectomycordectomy

Depression

FLI: Functional Living Index; STAI: State Trait Anxiety Inventory; HNQOL: Head and Neck Quality of Life; SF-36: Medical Outcome Short Form 36; SF-12: Medical Outcome Short Form 12; UWQOL: University of

Washington Quality of Life; RND: radical neck dissection; MRND: modified radical neck dissection; SND: selective neck dissection; PSS-HN: Performance Status for Head and Neck Cancer; VRQOL: Voice-Related

Quality of Life; EORTC-C30: European Organization for Research and Treatment of Cancer Core Questionnaire; EORTC-HN35: European Organization for Research and Treatment of Cancer Head and Neck Cancer

Module; CES: Center for Epidemiologic Studies Depression Scale; PAIS-SR: Psychosocial Adjustment to Illness Scale Self Report; MCPLQ: Mayo Clinic Postlaryngectomy Questionnaire.

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After chemotherapy and radiation therapyMany patients undergoing concurrent chemotherapyand radiation experience RTOG Grade 3– 4 mucositisthat usually requires a break in the radiation treat-ment. Other serious toxicities include hematologicand infectious complications that may lead to death.18

The acute side effects usually subside after treatment.General and physical functioning was reported to havereturned to the pretreatment baseline after 12months.70

Xerostomia and dysphagia were the most com-mon side effects reported with long-term follow-up(77% and 50%, respectively).71–73 Dry mouth andsticky saliva were the most troublesome long-termeffects reported in all studies. As a result of the xero-stomia and dysphagia, only 50% of the patients wereable to resume a normal diet after treatment.71 Resid-ual pain occurred in 15% of patients and was reportedto significantly alter their QOL.71 Depression was ob-served in 23% of patients and may have exacerbatedthe severity of the residual effects.

Other reported long-term side effects affecting theQOL were hoarseness, tasting impairment, and tris-

mus. Despite the severity of these treatment sequelae,which influenced the QOL negatively, long-term sur-vey results of the Veterans Affairs Laryngeal CancerStudy suggested that chemoradiation may result in abetter QOL outcome compared with the conventionaltreatment of surgery and postoperative radiation forpatients with advanced laryngeal carcinomas.74

Patients with TNM Stage III and IV laryngeal car-cinoma in that trial were randomized into two groups;induction chemotherapy was performed in bothgroups followed by either radiation therapy or surgeryand postoperative radiation. Survival was comparable,but among long-term survivors, those who hadachieved successful organ preservation in the chemo-radiation group were found to have a significantlybetter QOL compared with those patients who weretreated with surgery and radiation therapy. Patientswith preservation of the larynx reported less pain,better emotional well-being, and less depression.

The study suggested that chemotherapy and radi-ation may result in a better QOL compared with theconventional treatment of surgery and radiation be-cause of organ preservation. McDonough et al.,75 also

TABLE 2Factors Affecting Quality of Life Issues for Patients with Locally Advanced Head and Neck Carcinoma who Undergo Radiation Therapy

AuthorsNo. ofpatients Site

Type ofquestionnaire

Radiation dose(Gy) Type of issues

Hughes et al.45 50 Nasopharynx ESH Not specified Xerostomia,dysphagia

Huguenin et al.60 79 Oral cavity, larynx, oropharynx, nasopharynxhypopharynx

EORTC-C30EORTC-HN35

68–76.8 Xerostomia,eating,trismus

Allal et al.61 31 Larynx, hypopharynx PSSHNEORTC-C30

69.9 Xerostomia,speech

Hammerlid et al.62 105 Oral cavity, oropharynx, hypopharynx EORTC-C30EORTC-HN37HADS

Not specified Xerostomia,pain,nutrition,depression

Bjordal et al.63 245 Oral cavity, larynx, pharynx EORTC-C30EORTC-HNGHQ-20

63–66 Xerostomia,fatigue,emotion

Griffiths et al.64 615 Not specified RSCL HADS Not specified Anxiety,depression

Chawla et al.65 50 Oral cavity, oropharynx, nasopharynx, larynx BDIFLIC

70 Depression

Harrison et al.66 36 Base of tongue MSASFACTPSSSEQ

45–54 and implantup to 30

Xerostomiadysphagiapaininsomnia

Moore et al.67 49 Base of tongue PSS 73.8–79.2 Normalcy of dietWasserman et al.69 303 Oral cavity, oropharynx, larynx PBQ Up to 70 Xerostomia

Gy: grays; ESH: Eating and Swallowing History; EORTC-C30: European Organization for Research and Treatment of Cancer Core Questionnaire; EORTC-HN35: European Organization for Research and Treatment

Head and Neck Cancer Module; PSSHN: Performance Status Scale for Head and Neck Cancer; HADS: Hospital Anxiety and Depression Scale; GHQ-20: General Health Questionnaire, 20-item version; RSCL: Rotterdam

Symptom Checklist; BDI: Beck’s Depression Inventory; FLIC: Functional Living Index-Cancer; MSAS: Memorial Symptom Assessment Scale; FACT: Functional Assessment of Cancer Therapy; PSS: Performance Status

Scale for Head and Neck Cancer; SEQ: Sociodemographic and Economic Questionnaire; PBQ: Patient Benefit Questionnaire.

Combined Therapy for Head and Neck Malignancies/Nguyen et al. 1137

reported significantly higher QOL scores in the groupof patients with head and neck carcinoma who re-ceived chemotherapy and radiation compared withthose who were treated with induction chemotherapyfollowed by surgery and postoperative radiation. So-cial distress and avoidance were lower in the nonsur-gical group of patients because they had superiorcommunication abilities and less disfiguration. In an-other study, despite the poor prognosis associatedwith locally advanced head and neck hypopharynxtumors, Schrader et al. observed a locoregional controlrate of 71% with hyperfractionated radiation therapyand concurrent chemotherapy.73 Late sequelae oftreatment were tolerable and did not appear to havean impact on the survivors’ QOL. With the exceptionof two patients, swallowing function was preserved.Xerostomia and trismus were the most common long-term effects. Good functional outcome also was con-firmed by Huguenin et al. for long-term survivors ofadvanced head and neck malignancies who receivedchemoradiation.72 However, in that study, xerostomiawas the main factor responsible for the deteriorationof nutrition and poor social interaction.

The addition of amifostine could be beneficial inthis setting. Two randomized trials have shown a sig-nificant reduction of high-grade xerostomia in pa-tients undergoing chemoradiation or radiation for ad-vanced head and neck carcinoma who also werereceiving amifostine.76,77 The addition of amifostinedid not appear to have an impact on survival or local

control. Severe hematologic toxicity and high-grademucositis also were reported to be reduced with highdoses of amifostine (500 mg intravenously during che-motherapy). However, QOL issues were not addressedin chemoradiation trials and should be integrated infuture studies. Table 3 summarizes the QOL results inpublished studies of patients treated with chemora-diotherapy.

CONCLUSIONSPatients with advanced head and neck malignanciesoften have baseline dysfunction resulting from thedestruction of normal tissues by the tumors. Regard-less of the modalities of treatment (surgery, radiation,or chemoradiation), significant sequelae occur (e.g.,pain, depression, dysphagia, xerostomia, and bodyimage alteration).

Clinicians need to be aware of the long-term com-plications associated with treatment. Psychotherapyand emotional support are required for all patientswith head and neck malignancies. Preliminary studiessuggest that head and neck carcinoma patients withbetter self-confidence achieved a higher survival.78

Therefore, psychotherapy may have an impact notonly on QOL but also on survival.

Chemotherapy and radiation together were foundto produce significant acute toxicity that resolved aftertreatment. Current chemoradiotherapy studies sug-gest that QOL may improve with this combinationcompared with the conventional treatment of surgery

TABLE 3Factors Affecting Quality of Life Issues for Patients with Locally Advanced Head and Neck Carcinoma Who Undergo Chemotherapyand Radiation Treatment

AuthorsNo. ofpatients Site

Type ofquestionnaire Chemotherapy

Radiation dose(Gy) Issues

List et al.70 64 Oral cavitylarynxpharynx

PSS-HNMUHNRQFACT-HN

5-FU, HUCDDP

75 bid Xerostomia, taste, diet,dysphagia, pain

Huguenin et al.72 64 Oral cavitylarynxoropharynxhypopharynx

EORTC-C30EORTC-HN35

CDDP 74.4 bid Xerostomia, dysphagia,nutrition, socialinteraction

Schrader et al.73 41 Hypopharynx EORTC-HN35 5-FU, MTC 72 bid Xerostomia, dysphagia,trismus

Terrell et al.74 46 Larynx HNQOLSF-36BDI

5-FU, CDDP 70–76 Pain, depression

McDonough et al.75 24 Not specified UWQOLSADS

P, CP Not specified Social distress, socialavoidance

Gy: grays; PSS-HN: Performance Status Scale for Head and Neck Cancer Patients; 5-FU: 5-fluorouracil; HU: hydroxyurea; MUHNRQ: McMaster University Head and Neck Radiotherapy Questionnaire; bid: twice daily;

CDDP: cisplatin; FATC-HN: Functional Assessment of Cancer Therapy-Head and Neck; EORTC-C30: European Organization for Research and Treatment of Cancer Core Questionnaire; EORTC-HN35: European

Organization for Research and Treatment of Cancer Head and Neck Cancer Module; MTC: mitomycin C; HNQOL: Head and Neck Quality of Life; SF-36: Medical Outcome Short Form 36; BDI: Beck Depression

Inventory; UWQOL: University of Washington Quality of Life; P: paclitaxel; CP: carboplatin; SADS: Social Avoidance and Distress Scale.

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and postoperative radiation because of organ preser-vation. However, additional studies and long-term fol-low-up are needed to confirm these findings.

Xerostomia remains a major side effect in patientsundergoing radiation therapy. New treatment modal-ities may have an impact on this complication andQOL; the addition of amifostine reportedly decreasesthe incidence of severe xerostomia. Intensity-modu-lated radiation, which decreases the radiation dose tonormal tissues, may reduce the incidence of xerosto-mia and other side effects.79 Future clinical trialsshould address these issues.

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