[CANCER RESEARCH 53. 5113-5120, November 1, 1993]

Special Lecture

Recent Advances in Head and Neck Cancer—Larynx Preservation and Cancer

Chemoprevention: The Seventeenth Annual Richard and Hinda RosenthalFoundation Award Lecture1

Waun Ki Hong,2 Scott M. Lippman, and Gregory T. Wolf

Department of Thoracic!Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 f\V. K. H., S. M. L.¡;Department ofOtolaryngology, University of Michigan Medical Center, Ann Arbor, Michigan 48109 ¡G.T. W.¡;and the Department of Veterans Affairs Laiyngeal Cancer Study Group

Head and neck cancer is a major public health problem. In theUnited States alone, approximately 43,000 new cases of head andneck cancer will be diagnosed and 11,000 persons will die of thedisease in 1993 (1, 2). Worldwide, over 500,000 new cases of thiscancer occur yearly, and the incidence is rising. Furthermore, despiteintensive efforts in primary prevention, screening, and therapy, long-

term survival rates have not improved substantially since the 1960s.Standard treatment for head and neck cancers consists of surgery,radiotherapy, or both, and is met with mixed results. Standard treatment is frequently initially successful in early stage disease, but evenin early stage disease, initial success is tempered by the potential forlong-term development of deadly SPT.3 Against advanced disease,

standard therapy is less successful, generally producing cure ratesunder 50%. Standard local therapy of surgery and radiotherapy, evenwhen successful, can cause significant functional and cosmetic deformities, leading to a tremendous loss of quality of life. Despite improvements in reconstructive surgery and rehabilitation, patients whorequire total laryngectomy, glossectomy, or composite resection forcurative therapy suffer major lifelong debilities (1, 2). Furthermore,the treatment advances that extend these patients' lives are under

mined by the development of SPT (3, 4). The crucial therapeuticissues of severe morbidity and the significant rate of development ofSPT in "cured" head and neck cancer patients are responsible for the

emerging importance of two new approaches to these diseases, organpreservation and chemoprevention.

Advances in Organ Preservation: Laryngeal Cancer

Laryngeal cancer is the most common head and neck cancer, representing roughly 30% of all cases in the United States. The standardtreatment for locally advanced laryngeal cancer is total laryngectomyand postoperative radiotherapy (1, 2). Laryngectomy may be associated with impairments in smell, taste, and swallowing ability, butunquestionably, the major problem relates to the loss of naturalspeech. Laryngeal cancer patients are often willing to make tradeoffsbetween quality and quantity of life in order to preserve their larynx(5).

Although advances in surgical techniques have had some impact onmorbidity, primary chemotherapy for organ preservation is being investigated as an alternative to the surgical component of currentstandard therapy (1, 2).

Received 8/3/93; accepted 8/17/93.1Supported by USPHS Granls CA 46303, CA 16672, and POI CA 52051 from the

National Cancer Institute; the Department of Veterans Affairs Laryngeal Cancer StudyGroup; and the Charles A. LeMaistre Chair in Thoracic Medical Oncology. Presented atthe 84th Annual Meeting of the American Association for Cancer Research. Orlando, FL,May 19, 1993.

2 To whom requests for reprints should he addressed, at Department of Thoracic/Head

and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center,1515 Holcomhe Boulevard. Box 80, Houston, TX 77030.

3 The abbreviations used are: SPT, second primary tumors; UADT. upper aerodigestive

tract; RAR, retinoic acid receptors; 13cRA. 13-cu-rctinoic acid; TN. tumor-nodes status.

Historical Perspective. The first primary chemotherapy approaches in locally advanced head and neck cancer, begun in the early1970s, involved single-agent methotrexate. Survival after methotrex-

ate followed by definitive local therapy was no different than that afterstandard local therapy, nor did methotrexate increase morbidity. Thislack of increased morbidity highlighted the feasibility of this approachand encouraged investigators to use cisplatin in this setting when thehigh level of activity of this agent became known a little later in the1970s (6).

Investigators were excited by the striking early response rates oflocally advanced head and neck disease to combined cisplatin andbleomycin, 70-80% overall and 20-30% complete (1, 2, 6, 7). The

potential advantages of this primary chemotherapy approach wereevident; dramatic tumor shrinkage would greatly enhance surgical andradiotherapy cure rates and could achieve an important adjuvant effectby eradicating micrometastatic disease, substantially improving local-

regional control and reducing the incidence of distant métastases.Noone questioned that primary cisplatin-based chemotherapy would im

prove survival, only how great the improvement would be.A definitive phase III trial of primary cisplatin-bleomycin was

begun in 1978 (8). This three-arm, multicenter United States trialinvolving 462 patients was the first to capture widespread multidis-

ciplinary enthusiasm for primary chemotherapy in the head and neck.The trial included locally advanced resectable cancer of multiple headand neck sites and compared standard surgery-radiotherapy and twoexperimental therapies, primary chemotherapy (cisplatin-bleomycin)with and without maintenance cisplatin. Although begun with thehighest expectations, this trial culminated in 1982 by demonstratingthat these chemotherapy regimens did not increase the rates of disease-free or overall survival over those of the standard surgery-radio

therapy regimen.In 1983, the National Cancer Institute convened a conference of

investigators to determine whether there were any positive indicationsfrom the generally disappointing results of these primary chemotherapy trials. One of the most positive findings from all the data wasthat the minority of patients who achieved a major response and thenrefused subsequent surgery had survival rates similar to those ofpatients who received the planned surgery after chemotherapy. It wasthis subset analysis that provided the direction for continuing investigation and led to organ preservation becoming a major focus ofprimary chemotherapy strategies in head and neck cancer. The majorgoal of organ preservation studies with primary chemotherapy is toeliminate the need for surgery, thereby preventing loss of organ function or severe disfigurement without compromising survival.

The first studies specifically dealing with the role of primary chemotherapy for organ preservation were reported by Jacobs et al. andHong et al. in the mid 1980s. Jacobs et al. (9) treated 30 patients withcancers of several head and neck sites with chemotherapy. The 12patients who achieved histológica! complete responses then receivedradiotherapy only; the 18 patients who did not achieve complete

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responses were treated with standard surgery and radiotherapy. At 2years, the respective disease-free and overall survival rates for all 30

patients were 52 and 53%, while the survival rates for the 12 patients

who achieved histological complete responses and avoided surgerywere 60 and 70%, respectively. This study was small and nonrandom-

ized hut did suggest that surgery could be avoided without compromising survival in patients treated with primary chemotherapy whoachieved histological complete responses.

The study by Hong et al. (10) was the first to focus on primarychemotherapy and organ preservation specifically with regard to la-

ryngeal cancer and was among the first to report patterns of responsewith sequential chemotherapy-radiotherapy. The 46 patients analyzed

were treated on three primary chemotherapy protocols; reasons for nothaving surgery included patient refusal, doctor refusal, and medicalcontraindications. The report differed from the study by Jacobs et al.in that all patients who received sequential chemotherapy-radio

therapy were analyzed, regardless of chemotherapy response. Hongdocumented that chemotherapy response predicted radiotherapy response. Of 28 patients who achieved a partial response to chemotherapy, 22 (79%) achieved a complete response after radiotherapy. Incontrast, of 11 patients who achieved less than a partial response toprimary chemotherapy, only 2 (18%) achieved a complete responseafter radiotherapy (P = 0.0002). Hong et al. focused on the potential

great benefit, in terms of both morbidity and quality of life, of thisapproach for the 20 patients in the study with laryngeal or hypopha-ryngeal cancer who would otherwise have required total laryngec-

tomy. Of these 20 patients, 13 achieved partial responses after chemotherapy, and all 13 partial responders achieved a complete responseafter radiotherapy. The overall survival rate was similar to that reported with standard laryngectomy. This report extended the findingsof Jacobs et ai, which applied only to histological complete responses, and suggested the potential of this organ preservation strategy for all chemotherapy responders. The observations of Hong et al.led directly to the design of the Veterans Affairs (VA) trial, whichfocused on patients who would require laryngectomy for cure.

Concurrently with the studies of Hong et al., Jacobs et al., andothers, investigators at Wayne State University developed a regimencombining cisplatin and 5-fluorouracil. This appeared to be superior toother cisplatin-based regimens, producing complete response rates as

high as 54% after three courses in locally advanced disease (1, 2, 11).Even though none of the primary chemotherapy trials had pro

longed survival, they did demonstrate the feasibility of this approachand that chemotherapy response predicts radiotherapy response. Inaddition, they suggested that this approach might reduce treatmentmorbidity. These silver linings of an otherwise negative collection ofdata led to a highly significant multicenter trial specifically designedfor organ preservation.

The Veterans Affairs Laryngeal Cancer Study Group Trial. Inthe early 1980s, the VA Laryngeal Cancer Study Group designed aprospective randomized phase III trial to compare survival rates inpatients with resectable stage III or IV laryngeal cancer treated withsequential chemotherapy and radiotherapy, or with a standard treatment of laryngectomy and postoperative radiotherapy (12). The hypothesis for this study was that combined chemotherapy-radiotherapy

could achieve equivalent survival rates with better quality of life(larynx preservation and function) than total laryngectomy and radiotherapy for patients with advanced laryngeal cancer.

Laryngeal cancer was the primary site selected for the study because of the very debilitating functional and psychosocial effects ofthe loss of natural speech (5). In addition, many laryngeal cancerpatients were reluctant to undergo radical surgery and were alreadychoosing radiation alone with surgical salvage. Therefore, the timing

for a definitive phase III study seemed appropriate. This is the largeststudy yet to be performed of a single site within the head and neck.

This trial compared treatment with induction chemotherapy (cisplatin, 100 mg/irr/day, and 5-fluorouracil, 1 g/irr/day for 5 days, forthree cycles) plus sequential definitive radiotherapy (66-76 Gy to the

primary tumor site) to treatment with standard surgery and postoperative radiotherapy (50-60 Gy). Patients randomized to receive in

duction chemotherapy underwent response assessment after twocycles of cispIatin-5-fluorouracil. Those achieving at least a partial

response received a third cycle, followed by definitive radiotherapy,followed by direct laryngoscopy and primary tumor site biopsy todetermine histological response. In this group, surgery was reservedfor later salvage of persistent or recurrent disease. Nonresponders toinduction chemotherapy (those who had a tumor response of <50%)underwent immediate surgery followed by radiotherapy (Fig. 1).

The specific design feature of immediate surgical salvage afterfailure of two cycles of chemotherapy was based on three key issues.(a) This approach minimized the delay in performing surgery andtherefore improved chances for survival, (b) radiotherapy is frequently less successful after chemotherapy failure, (c) morbidity isoften increased after full dose chemotherapy and radiotherapy andmay prevent definitive resection.

Between 1985 and 1989, a total of 332 patients from 14 VA hospitals were enrolled, and equal numbers were assigned to the surgery-radiotherapy arm and chemotherapy-radiotherapy arm. The two arms

were balanced with regard to major prognostic factors, including stage(III, IV), TN subset, laryngeal subsite, vocal cord fixation, thyroidcartilage invasion, and performance status. The quality of the studyand compliance rate were high; only 2% of randomized patients werelost to follow-up. Currently, the median follow-up is 60 months(range, 12-90 months).

After two cycles of induction chemotherapy, 85% of patientsachieved a major response at the primary tumor site (31% completeresponse). After three cycles of chemotherapy, the overall responserate was 98% (49% complete), and 64% of patients had a pathologicalcomplete response (i.e., a histologically negative biopsy at the primary tumor site).

The estimated 3-year survival rates were 56% (48-64%) for surgery-radiotherapy and 53% (45-61%) for chemotherapy-radiotherapy

(Fig. 2). There were no significant differences in survival based onsubsite within the larynx (glottic or subglottic), stage (III or IV), orresponse to chemotherapy (13). The data indicate that the short delayin definitive surgery in the chemotherapy nonresponders was notdetrimental. The duration of survival of the 18% of patients whounderwent salvage laryngectomy immediately after one or two cyclesof chemotherapy (because of either a poor response or an inability totolerate chemotherapy) was similar to that in the group that receivedinitial surgery-radiotherapy. Although early surgery can effectively

salvage local disease in most chemotherapy nonresponders, recurrentdisease is often unresectable in patients who have been treated with

SiteStage

RAND0

MZEChemotherapy

s-—¿�^- Response —¿�^~(2 cycles) \ (1cycle)/No

nvResponseV

\\Surgery»•\\Radiation

/Therapy\RadiationTherapyRadiationTherapyComplete/

ResponseResidualDisease\Surgery

Fig. 1. Trial design for the VA laryngeal cancer study.

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so.

1.0

0.8

0.6

0.4

0.2

0.010 20 30 40 50 60 70 80 90

MonthsFig. 2. Survival curves for VA laryngcal cancer study: arms of surgery-radiotherapy

( ) and chemotherapy-radiotherapy ( ).

chemotherapy-radiotherapy, and these patients have higher surgical

complication rates (e.g., major wound infections) than patients whohave surgery after chemotherapy alone.

Sixty-two percent (103 of 166) of patients in the chemotherapy arm

were able to preserve their larynxes. Furthermore, 66%, or 52 of the79 surviving chemotherapy-radiotherapy patients, are still able to

communicate using their natural speech. The function (i.e., speech andswallowing) of the retained larynx in these patients is being systematically studied by rigorous speech assessments (speech intelligibility,acceptability, reading rate, vowel duration, and general communication profile). Initial evaluation of patients up to 2 years after therapyindicated that the chemotherapy-radiotherapy group had significantlybetter speech than the artificial speech achieved in the surgery-radiotherapy group. In addition, patients in the chemotherapy-radiotherapyarm experienced less difficulty swallowing. Chemotherapy-associated

toxic effects were acceptable and did not interfere with subsequentradiotherapy or surgery.

Given these recent survival and larynx preservation rates, selectedpatients with locally advanced laryngeal cancer now have the optionof preserving their voice box without risking shorter survival.

Significant differences between study arms were evident in thepatterns of first treatment failure: primary site recurrence was morefrequent in the chemotherapy-radiotherapy arm and distant metastasiswas more frequent in the surgery-radiotherapy group. There were no

significant differences in regional node recurrence rates between thetwo study arms. The significant difference in patterns of failure disappeared over time when all sites of tumor recurrence (first andsubsequent sites) were considered (i.e., many chemotherapy-radio

therapy patients who had first relapsed locally were effectively salvaged surgically but later developed distant metastasis). The differences in first site failure patterns are explained by the fact that theprimary local site (the larynx) was removed in the surgery-radio

therapy group, thereby greatly reducing local recurrence rates in thisgroup. Ultimately, therefore, the overall rates of distant métastaseswere the same in the two arms. The time to first developing distantmétastases,which would indicate whether chemotherapy delayed thedevelopment of distant métastases,has not been analyzed.

Two critical components of organ preservation trials involving primary chemotherapy-radiotherapy are careful patient surveillance after

chemotherapy and early surgical salvage for nonresponders to initialchemotherapy. This successful application of primary chemotherapy-radiotherapy in preservation of the larynx opens new avenues forapplication of this strategy in patients with locally advanced cancer ofother head and neck primary sites.

Although equivalent to that of surgery-radiotherapy, the 3-year

survival rate of approximately 50% for patients who received chemotherapy-radiotherapy is unacceptable. Alternative strategies that will

preserve organ function and prolong survival need to be investigated.Strategies now being tried include concomitant chemotherapy-radio

therapy, altered radiotherapy fractionation schedules, early plannedneck dissection (in the absence of response to chemotherapy foradvanced nodal disease) for enhanced local-regional control, and intensive multiagent chemotherapy for the treatment of distant micro-

metastases.An unresolved issue raised by the positive results of the phase III

VA trial is whether the rate of laryngeal preservation after primarychemotherapy-radiotherapy is superior to that after primary radio

therapy alone. A primary radiotherapy arm was not included in the VAtrial: this therapy was not considered standard or ethical because, inhistorical comparisons with surgery-radiotherapy studies, it appeared

to have yielded lower survival rates. No phase III trial has comparedprimary radiotherapy (with surgical salvage) with standard surgery-

radiotherapy, although both approaches have been available for decades. Although several single-arm trials of primary radiotherapy inselected patients with T^N,, disease have reported 5-year survival ratesequivalent to those of surgery-radiotherapy (1, 2), many studies

strongly suggest that primary radiotherapy is less effective than primary surgery for the more advanced disease which characterized theVA study population; the approximately one-half with stage IV dis

ease, 25% with T4 lesions, and 50% with nodal disease (many withadvanced N2.3 disease) would apparently have been unlikely to dowell with primary radiotherapy alone.

Early phase III results from other chemotherapy-radiotherapy stud

ies, including a large French study, appear to confirm the VA trial andsuggest a role for this approach in other head and neck sites (14).

Fifteen years after induction chemotherapy was introduced into thetreatment of head and neck cancer, an intergroup study was developedbased on the findings of the VA Laryngeal Trial. This will be the firsttime in history that a trial has been developed for advanced laryngcalcancer patients which does not use initial laryngectomy as standardtreatment. The new multicenter phase III three-arm trial includes theexperimental sequential chemotherapy-radiotherapy arm from the VAtrial, a concomitant chemotherapy-radiotherapy arm, and a third radiotherapy-only control arm, which will resolve the radiotherapy versus chemotherapy-radiotherapy issue by direct comparison (Fig. 3).

To accommodate the radiotherapy arm. this study differs from the VAtrial in several key areas, including patient eligibility (excludes T4)and treatment plan (patients with nodal disease have elective neckdissection after completing primary therapy).

Advances in Chemoprevention

Chemoprevention is a relatively new approach for controlling cancer of the UADT. Chemoprevention is defined as the use of specificnatural or synthetic chemicals to reverse or suppress premalignantcarcinogenic progression to invasive malignancy (15-18).

Reviewed in this section are the biological concepts of Chemoprevention (multistep and field carcinogenesis and mechanisms of reti-

CompieteJ Response

•¿�Radiation fTherapy V

ResidualDisease

\- Radiation Surgery

Therapy

Radiation Therapy

Fig. 3. Trial design for the current intergroup organ preservation study in laryngealcancer.

STRATIFYSiteStageRAND0M1ZEChemotherapy,

—¿�»-Response(2 cycles) \ (1cycle)s

X/No/

Response(

\YVSurgery-\\\

Radiation Therapy - Cispl

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noid action) and the record of randomized chemoprevention trials inthe head and neck.

Biology

Understanding the biology of carcinogenesis is crucial to the development of effective chemoprevention. Two basic concepts supporting chemoprevention are the multistep nature of carcinogenesis andthe diffuse field-wide carcinogenic process.

Multistep Carcinogenesis. Epithelial cancer appears to develop ina recognizable and predictable series of steps. Epithelial carcinogenesis is conceptually divided into three phases: initiation; promotion;and progression. Evidence of multistep carcinogenesis is well documented in many animal models. This process has also been inferredfrom human studies identifying clinical-histological premalignant le

sions (e.g., leukoplakia, metaplasia, and dysplasia) associated withmalignant transformation rates of up to 30-40% (19, 20).

This concept has recently been analyzed in molecular studies whichhave identified a continuum of accumulated specific genomic alterations that take place in the clonal evolution of epithelial neoplasia.The molecular genetic basis of the multistep process in humans ismost apparent in the progression of adenoma-carcinoma in the colon.

This progression follows a sequence of events from ras mutationthrough allelic losses on chromosomes 5q, 17p, and 18q, each event,or step, followed by clonal expansion (21). Multiple genetic events inother epithelial sites have been identified and are beginning to besequenced. In the UADT, numerical (e.g., polysomy of 7 and 17) andstructural (e.g., deletions of 3p and 18q) chromosome alterations havebeen detected in various histological stages of UADT carcinogenesis,including in "benign" epithelium adjacent to tumor (1, 2, 22). Specific

molecular genetic alterations detected in premalignant UADT lesionsinclude mutations of p53, reduced expression of RAR-ß,and increased expression of c-erbBl, TGF-a, and c-myc (4, 23-27). Mutations of Ras and amplification of int-2, hst-1, and bcl-1 have currently

been identified only in UADT cancers (1, 2).Field Carcinogenesis. The seminal concept of field carcinogenesis

was proposed by Slaughter et al. (28) in 1953. This concept proposesthat multiple neoplastic lesions of independent origin occurring withinan epithelial field can result from repeated exposure to a single carcinogen. Patients with cancer of the head and neck or lung, or who areat high risk of developing these cancers, most commonly have ahistory of exposure to cigarette smoke and are likely to have multipleclinically and histologically evident premalignant lesions within theaerodigestive tract (29). According to the field carcinogenesis theory,primary tumors and related SPT result from progression of commonlyinitiated, although genetically different, premalignant lesions.

Recent molecular genetic studies of histologically normal and premalignant epithelia from high-risk subjects and of malignant aerodi

gestive tract epithelia strongly support the field carcinogenesis concept. These studies suggest that multiple, genetically distinct lesionsoccur throughout the aerodigestive tracts of high-risk subjects and

cancer patients. Studies of histologically normal and premalignantepithelia of the UADT and lungs of high-risk subjects detect multiple

genetic abnormalities throughout these epithelial fields, including p53mutations, 3p deletions, and aneuploidy, which are inferred to be earlysteps in the carcinogenic progression toward malignancy (22, 30-32).

The field carcinogenesis concept suggests that separate primarycancers that develop in a tissue region exposed to the same carcinogens would arise as independent clones with similar but unique molecular genetic alterations. Chung et al. (33) analyzed p53 mutationsin 31 patients with primary head and neck cancers and related SPT byusing single-strand conformation polymorphism. p53 was selected as

the molecular probe for this study because mutations of this gene are

known to be critical and common events in head and neck and otherepithelial cancers (30, 31, 34-36). Twenty-one patients were found to

have at least one p53 mutation, and in all cases the mutation wasdiscordant. Mutations were found in only one of the primary tumorsin 16 patients; of the 5 patients in whom mutations were found in bothprimaries, 4 had mutations in different exons within the p53 gene, and1 had mutations in different codons of the same exon by polymerasechain reaction sequence analysis. The class of p53-base mutations

(transitions) was the same in more than 70% of these primary tumorsand related SPT. These class-related but distinct mutations of p53 irf

primary tumors and SPT provide strong molecular support for fieldcarcinogenesis.

Neoplastic initiation by a common carcinogen is suggested by thehigh rate of mutations of p53 and by the similarity in the class ofmutations. However, the discordant nature of the mutations indicatesthat SPT may arise as independent genetic events. These and othergenetic and chromosomal alterations reveal that aerodigestive tractepithelia of high-risk subjects and cancer patients contain generalized

and dynamic genetic instability which is associated with profoundphenotypic alterations (22, 30-32, 37, 38).

Slaughter et al. based the field carcinogenesis concept on theirstudy of surgical specimens of tissue surrounding oral tumors. Theprofound histological changes that occurred in this surrounding tissueranged from mild hyperplasia to severe dysplasia and invasive cancer.Slaughter et al. reported that these changes occurred over a wide areawhich included clinically normal-appearing tissue.

This work, done over 40 years ago, laid the foundations for thetechnologically advanced molecular studies of field carcinogenic effects that we and others are currently conducting (22, 25, 30, 31, 38).As did Slaughter et al., we have examined surgical specimens oftissues surrounding head and neck tumors in addition to specimens ofthe tumors themselves, and we have observed many genotypic andphenotypic changes in these tissues.

The new methods allow us to pursue the subtlest molecular signs offield carcinogenesis not only in histologically abnormal tissues butalso in histologically normal epithelia within the high-risk field. The

markers we have studied to date are polysomies of chromosomes 7and 17, mutations of p53, nuclear RAR, epidermal growth factorreceptor, and proliferating cell nuclear antigen (22, 25, 37). Changesin these molecular and cellular markers are being compared with thehistological yardstick of carcinogenic changes. Except for RAR, allthe markers mentioned above change in direct relationship with histological stage; RAR-ßchanges inversely.

These results support the concept that cancers of the UADT areassociated with field carcinogenesis and develop in a multistep process. Current work is attempting to correlate specific genetic events(e.g., gene amplification or mutation) with altered phenotype (38).These and other findings suggest that mutated p53 and other suchgenetic changes can appear early in multistep head and neck carcinogenesis (i.e., in histologically normal high-risk tissue) and may serve

as useful biomarkers of cancer risk and of response in chemoprevention trials (4, 39).

Clinical Trials

Chemoprevention trials in the head and neck have been conductedin two major disease systems. The earliest trials were conducted in thetreatment of oral leukoplakia, a premalignant lesion. Positive results inthis disorder led to subsequent clinical trials in the related setting ofpreventing SPT after primary cure of head and neck cancer.

Oral Premalignancy: Primary Chemoprevention. Oral premalignant lesions are characterized clinically by white (leukoplakia) orred (erythroplasia) mucosal lesions in the oral cavity or oropharynx

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that cannot be scraped off or classified as any other disorder. Theselesions are generally tobacco-related precursors of squamous cell car

cinoma, are easily monitored, and have useful preclinical models. Oralpremalignancy, therefore, is an excellent system for chemopreventionstudy because of its etiological, biological, and regional relationshipthrough field carcinogenesis to aerodigestive tract cancers (39).

Surgical removal or laser excision are the standard therapies forpatients with oral leukoplakia, but local treatment is often not usefulin patients with extensive multiple lesions and does not treat the widefield of high-risk tissue (1, 2).

Several single-arm trials have suggested that various agents haveactivity against oral leukoplakia. These agents include ß-carotene,

vitamin E, and selenium (39, 40). Although all three agents haveproduced promising results, none has undergone randomized placebo-

controlled testing to establish activity. The only class of agents thathas emerged from single-arm testing into randomized trials is the

retinoids (39, 41).Five randomized studies of retinoids have been conducted in oral

leukoplakia. In late 1982, we developed the first randomized chemoprevention trial of primary therapy in oral leukoplakia, a short-term,placebo-controlled, double-blinded study of high-dose 13cRA (1-2

mg/kg/day). The 44 participants in this study received treatment for 3months, followed by 6 months of follow-up. We found that the reti-noid treatment reversed leukoplakia lesions both clinically and histo-logically in over one-half of the treated patients. The clinical (complete-plus-partial) response rate was 67% (16 of 24) with 13cRA and10% (2 of 20) with placebo (P = 0.0002). Dysplasia was reversed in

54% (13 of 24) who received 13cRA and 10% (2 of 20) who receivedplacebo (P = 0.01). The toxicity of high-dose 13cRA was, however,

unacceptable for use in the general population. Also, more than 50%of the responding patients relapsed within 2-3 months of treatment

cessation (42).This study established the short-term activity of high-dose 13cRA

in inducing remission of oral leukoplakia and revealed that thistherapy resulted in unacceptable toxic effects and a high relapse rate.These results led us to design and conduct the first randomized maintenance trial of less toxic therapy in patients with oral leukoplakia(43). This trial randomized patients whose lesions responded or remained stable following high-dose 13cRA induction therapy (1.5 mg/

kg/day for 3 months). The study group was then randomly assigned toreceive maintenance therapy with low-dose 13cRA(0.5 mg/kg/day) orß-carotene(30 mg/day) for 9 months.

A total of 70 patients were enrolled in this National Cancer Institutetrial. Following the induction phase, the clinical response rate was55%, which was consistent with the results of our earlier study;furthermore, the degree of dysplasia was reduced in 43% of patients.

Following the maintenance phase, only 8% of the patients (2 of 24)in the low-dose 13cRA group progressed, whereas 55% (16 of 29) ofpatients in the ß-carotenegroup progressed (P < 0.001). The rate ofresponse to maintenance therapy beyond that achieved with high-dose

induction therapy was also higher in the 13cRA group (33%) than inthe ß-carotenegroup (10%). Disappointingly, invasive or in situ carcinoma has developed in seven patients from the ß-carotenegroup andin one patient from the low-dose 13cRA group. Furthermore, although

the toxic effects in the maintenance phase were fairly mild, they werestill significantly greater in the low-dose 13cRA group than in theß-carotenegroup. Adverse reactions in the low-dose 13cRA group

included dry skin, cheilitis, conjunctivitis, and hypertriglyceridemia.Two subsequent randomized trials in leukoplakia are supportive of

the retinoid activity achieved in our primary therapy trial. A placebo-controlled 6-month study of natural vitamin A by Stich et al. (44)

achieved significantly higher complete remission rates and lower progression rates in the oral lesions of 54 Asian betel nut chewers. A

4-month placebo-controlled study by Han et al. (45) of a synthetic

retinamide achieved significant primary clinical activity.A recent interim analysis from an ongoing randomized maintenance

trial is supportive of the results of our earlier maintenance trial. Underway in Italy, this trial is comparing the efficacy of a synthetic retinamide (fenretinide) in preventing relapse after excision of a lesionswith the efficacy of no treatment. The current analysis of 71 évaluablepatients indicates significantly lower relapse rates in the retinoid arm(46). Both our and the Italian trials are remarkably similar in havinglow retinoid-arm relapse rates, 8 and 7.7%, respectively, and in havingsignificantly greater control-arm relapse rates, 55 and 29%, respec

tively.Although five randomized trials have demonstrated significant ac

tivity of retinoids in reversing oral premalignancy, caution must beexercised before drawing overly optimistic conclusions from theseresults: (a) whereas the presence of oral leukoplakia is associated withan increased incidence of transformation to oral cancer, the reversal ofthese lesions has not been demonstrated to reduce the risk of developing cancer, the ultimate goal of chemoprevention; (b) there is noestablished optimal dose and schedule or specific retinoid for use inreversing oral premalignancy; (c) surgical or laser resection frequentlyis used successfully in the management of oral leukoplakia, and sofurther studies will have to assess when chemoprevention shouldreplace or adjoin standard local therapy.

Work in the laboratory is keeping pace with the clinical trials infurthering the development of retinoids for chemoprevention. In 1987,two independent research groups discovered a nuclear retinoic acidreceptor within the well-understood steroid receptor family (47). In

tensive subsequent research discovered two distinct classes of retinoicacid receptors (RAR and RXR) and that these receptors may mediatethe biological effects of retinoids by modulating gene transcription(48). Further in vitro and in vivo studies by Lotan et al. indicated thatthe expression of one RAR subtype, the ß-receptor,is greatly reduced

in late stage carcinogenesis of the head and neck (49). These researchers also observed that low expression of RAR-ßin cancer cell linescould be up-regulated by the addition of a retinoid.

Lotan's group then conducted new studies to determine whether

expression of RAR-ßis also low in vivo in human oral premalignancyand whether retinoid therapy would affect RAR-ßexpression in these

lesions (43, 49). They used in situ hybridization with antisense RNAto detect mRNAof RAR in biopsy specimens from premalignant orallesions.

In accordance with the primary hypothesis, the pretherapy analysesby Lotan et al. indicated that RAR-ßexpression was below normal in

premalignant lesions. Of the utmost importance was that the analysesconducted after therapy indicated that this expression increased significantly and correlated with lesion response to 3 months of inductionwith high-dose 13cRA. These results imply that the loss of expressionof RAR-ßis involved in the development of head and neck cancer and

suggest the provocative possibility that retinoid chemopreventive activity in the UADT is related to up-regulation of RAR-ß(4).

Oral premalignancy is a unique in vivo model system for the studyof retinoid mechanisms of action: retinoid clinical-histological activ

ity is established in this system, and tissue for mechanistic studies canbe obtained from the oral cavity easily and virtually noninvasively(39). The RAR-ßstudy by Lotan et al. and the related prospectiveclinical trials within this model system offer a paradigm of laboratory-

clinical interaction in the field of chemoprevention. This interactivework illustrates the potential for making highly significant discoveriesthat could not be made by either clinical trials or laboratory cell linestudies alone.

Second Primary Tumors: Adjuvant Chemoprevention. The rationale for using retinoids adjuvantly to prevent the development of

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HEAD AND NECK CANCER

SPT is based on the field carcinogenic link of SPT to oral premalig-

nancy (in which retinoids are highly active) and the high incidenceand rate of mortality from SPT (39). Prospective SPT rates in head andneck cancer are approximately 5-7%/year; SPT are the major cancer-

related cause of death in patients with early stage disease (3, 4). Localtherapy (surgery or radiotherapy) does not address the field-wide

carcinogenic process that can lead to the development of SPT throughout the aerodigestive tract. The integration of effective chemopreven-

tion to follow curative primary therapy would address the seriousproblem of SPT development and would be a major advance in thecontrol of head and neck cancers.

We prospectively studied 103 stage I-IV (Mn) patients (50). After

definitive treatment, these patients were randomized to receive eitherhigh-dose 13cRA or placebo for 12 months. The first 44 patientsreceived 13cRA at a dose of 100 mg/m2/day. Because 13 of them

required reduction to 50 mg/irr/day secondary to toxic effects, theprotocol was revised for the remaining 59 patients, who were begunat a dose of 50 mg/m2/day. The major end points of this adjuvant trial

were primary disease recurrence (local, regional, or distant) and thedevelopment of an SPT.

We found that 13cRAhad no impact on primary disease recurrence.However, patients in the 13cRA group had significantly fewer SPTthan patients in the placebo group, suggesting that in this setting,single-agent 13cRA is effective in suppressing or abrogating prema-

lignant foci but cannot eliminate fully transformed cancer cells.The initial report of this study, after a median follow-up of 32

months, indicated that high-dose 13cRA significantly reduced the rateof development of SPT (P = 0.005). The median follow-up is now 55

months (51). Two years after starting 13cRA, the protective retinoideffect on all SPT decreased, which suggests that the chemopreventiveeffect is reversible. Despite the fact that the annual overall SPT rateshave evened out, the cumulative number of patients with SPT in thetwo arms remains different, although the difference is less significantthan it was (P = 0.04). Subset analysis of only tobacco-related SPT

rates indicates a persistent retinoid effect at the same level of statistical significance.

Reduced SPT rates notwithstanding, 13cRA did not significantlyprolong survival over that in the placebo group. Several factors contributed to this: similar rates of primary disease recurrence (local,regional, or distant) in both arms; a high dropout rate related to toxiceffects in the 13cRA arm; and prolonged survival in patients whodevelop SPT (which develop more frequently in the placebo group)due to early detection and therapy.

The higher rate of multiple SPT in the placebo-treated patients than

the 13cRA group strongly supports the field carcinogenesis conceptand the evidence of the systemic activity of 13cRA. Further clinicalsupport of field carcinogenesis comes from the fact that over 80% ofSPT of the squamous cell carcinoma histológica! type occurred withinthe carcinogen-exposed field at risk (head and neck, lung, or esopha

gus). There was no correlation between SPT rates and smoking statusin this trial, in a recent prospective lung study, or in the oral leuko-

plakia trials (4). This apparent lack of smoking effect may reflect thelate stage of carcinogenesis, the relatively short follow-up, and/or the

small sample sizes of these studies. Since noncompliers were includedin the SPT analyses, the substantial toxicity-related noncompliance

rates in the retinoid group underscore the significant results of adjuvant 13cRA.

These important findings are being extended in a large-scale trial of

adjuvant chemoprevention in early stage head and neck cancer patients, in whom SPT are the major cancer threat to long-term survival.This comprehensive double-blinded, placebo-controlled, phase III

trial differs in design from our first trial in two major regards. Thecurrent study includes only early stage head and neck cancer patients,

who are at high risk of developing SPT. It also includes a lower doseof 13cRA which was determined from the activity and toxicity resultsfrom our recent randomized leukoplakia maintenance study (Fig. 4).

The applicability of these head and neck findings to other tobacco-related cancers is suggested by a recent report by Pastorino el al. (52,53) of a randomized study of high-dose vitamin A adjuvant therapy instage I non-small cell lung cancer. The lung findings are remarkably

similar to those of the head and neck cancer study. In both studies,over 70% of SPT occurred in the tobacco-exposed field, and the timeto development of a tobacco-related SPT was significantly longer irr

the retinoid arms. The rates of primary disease recurrence (local,regional, or distant) were not significantly different between the arms.Neither study was associated with prolongation of survival, however,which in part reflects effective surgical salvage of SPT in these prospectively followed patients. A United States intergroup trial using adesign similar to that of the head and neck trial is testing the ability oflow-dose 13cRA to prevent SPT in stage I non-small cell lung cancer

(4)-The results of the lung and head and neck studies that used rigorous

criteria applied to prospectively followed patients suggest that theproblem of SPT in patients with head and neck or lung cancer maycurrently be underrated. Although the data are limited, it seems significant that prospective studies have reported SPT rates for head andneck and lung cancer that are roughly 2-fold higher than retrospective

or tumor registry data (4).

Conclusion

The limited impact of standard therapy (chemotherapy, surgery, orradiotherapy) on survival, the morbidity resulting from surgical control, and the ominous threat of SPT faced by "cured" patients provide

the impetus for the intensive ongoing efforts to establish greatercontrol over head and neck cancer. Substantial progress has beenmade. Voice preservation has been achieved with primary chemotherapy-radiotherapy in most cases of locally advanced laryngeal can

cer without compromising survival. Although voice preservation improves the quality of survival, survival itself in these cases has notbeen prolonged. Ongoing studies aimed at enhancing local-regional

and distant control may translate into the ultimate goal of improvedsurvival rates for head and neck cancer patients.

Chemoprevention research is producing promising results with theretinoid 13cRA in the UADT. The ability of 13cRA to reverse pre-

malignancy and prevent SPT brings this chemopreventive agent to thethreshold of becoming standard therapy for fieldwide multifocal disease. Before it can be accepted as a standard, however, this agent's

ultimate efficacy (i.e., impact on survival rates), toxicity, and integrative role with currently standard therapies will need to be resolved.

Leukoplakia (NEJM 1986)82 1985

High-Dose 13CHA

Biomarker Studies

Leukoplakia1992-

Low-Dose 13cRA(NCI CA52051)

Leukoplakia (NEJM 1993)1988 1992

Low-Dose 13CRA(NCI CA46303)

Adjuvant (NEJM 1990) Second Primary

High-Dose 13cRA-1989 1991-

Low-Oose 13cRA(NCI CA52051)

Fig. 4. Series of completed and ongoing randomized head and neck cancer chemoprevention trials at M. D. Anderson Cancer Center. NEJM, New England Journal of Medicine; NCI. National Cancer Institute.

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HEAD AND NECK CANCER

Some of the most exciting new research in the head and neck iscoming out of the laboratory. Recent molecular studies have detectedspecific genetic changes in specimens of high-risk UADT tissue that

are histologically normal. These observations of genetic changes provide the strongest evidence supporting the concepts of multistep andfield carcinogenesis and may cause premalignancy to be redefined interms of molecular rather than clinical-histological criteria. Molecularbiomarkers may serve ultimately as intermediate end points for che-

moprevention trials (54).Extremely valuable findings are coming from laboratory studies

that are integrated within clinical trials. RAR-ßwas identified by

purely basic laboratory research; its expression was observed to bereduced in human head and neck cancer cell lines and tumor specimens. Later laboratory-clinical collaborative work confirmed that expression of RAR-ßis reduced in human premalignant tissue specimens and revealed that retinoid chemopreventive therapy can up-regulate RAR-ßexpression in association with response to the agent.

The highly inventive and productive collaboration between laboratory and clinical researchers in cancers of the head and neck shouldhasten the achievement of better prevention and control of thesecancers. This collaboration also may provide a paradigm for futurestudy of cancers of other sites.

Acknowledgments

12.

13.

15.

16.

17.

18.

1').

20.

21.

22

25.

26.

I am highly honored to be the recipient of this year's Richard and Hinda

Rosenthal Foundation Award, and I would like to express my appreciation toall the memhers of the AACR's Rosenthal Award Committee, as well as to Mr.

and Mrs. Rosenthal. I also wish to gratefully acknowledge the following people 24.for their contributions to the many studies summarized in this paper: SusanFisher; Helmuth Goepfert, M.D.; Walter Hittelman, Ph.D.; T. C. Hsu, Ph.D.;Loretta Uri, M.D.; Daniel Karp, M.D.; Irwin Krakoff, M.D.; Jin Soo Lee, M.D.;Reuben Lotan. Ph.D.; Lesa Nelson; Stimson Schantz. M.D.; Dong Moon Shin,M.D.; Margaret Spitz, M.D.; and Robert E. Wittes, M.D.

Finally. I would like to thank my brother. Dr. Suk Ki Hong, who is totallyresponsible for my education, and also my family, who have consistently givenme strong moral support and encouragement.

28.

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1993;53:5113-5120. Cancer Res   Waun Ki Hong, Scott M. Lippman and Gregory T. Wolf  Annual Richard and Hinda Rosenthal Foundation Award LecturePreservation and Cancer Chemoprevention: The Seventeenth

Larynx−−Recent Advances in Head and Neck Cancer

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