second primary malignancy of the aerodigestive tract in patients treated for cancer of the oral...

SECOND PRIMARY MALIGNANCY OF THE AERODIGESTIVETRACT IN PATIENTS TREATED FOR CANCER OF THE ORALCAVITY AND LARYNX

Karen Lin, MD, Snehal G. Patel, MD, Pen Yuan Chu, MD, Jeannette M. S. Matsuo, MD,Bhuvanesh Singh, MD, Richard J. Wong, MD, Dennis H. Kraus, MD, Ashok R. Shaha, MD,Jatin P. Shah, MD, Jay O. Boyle, MD

Head and Neck Service, Department of Surgery, P. O. Box 285, Memorial Sloan-Kettering Cancer Center,

1275 York Avenue, New York, New York 10021. E-mail: [email protected]

Accepted 16 April 2005

Published online 1 November 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20272

Abstract: Background. We aimed to identify patterns and

predictors of second primary malignancy (SPM) of the aero-

digestive tract (SPMADT) in patients with squamous cell

carcinoma of the oral cavity (SCCOC) and larynx (SCCL).

Methods. One thousand two hundred fifty-seven patients

from two existing databases were studied: 595 with SCCOC

(1986–1995) and 662 with SCCL (1984–1998). The primary

endpoint of interest was development of SPMADT, defined as

a second primary neoplasm of the head and neck, esophagus,

or lung.

Results. The 5-year SPMADT rate was 8% in the SCCL ver-

sus 10% in the SCCOC subgroup. Lung SPM was more com-

mon in the SCCL group; head and neck SPM was more common

in the SCCOC group. Smokers had a fivefold increased risk,

whereas alcohol use was associated with a twofold increased

risk of SPMADT.

Conclusions. The rates of SPMADT after treatment of

SCCOC and SCCL are comparable, but the patterns are

different. Smoking and alcohol use are independent predictors

of SPMADT development. A 2005 Wiley Periodicals, Inc. Head

Neck 27: 1042–1048, 2005

Keywords: neoplasms, second primary*/therapy; neoplasms,

second primary/epidemiology*; lung neoplasms/epidemiology;follow-up studies; survival analysis

Patients with head and neck cancer are inher-

ently at an elevated and constant risk for the

development of second primary malignancies

(SPMs).1 This elevated risk has been attributed

to carcinogen exposure, most notably tobacco

smoking and alcohol use. The addition of alcohol

to tobacco exposure contributes to the formation

of primary tumors and SPM development in the

mouth and pharynx rather than the larynx.

Patients who have index primary oral cancer

are more likely to have upper aerodigestive tract

(UADT) SPM develop, whereas those with index

larynx cancers are more likely to have pulmonary

SPM develop. Although some information in

existing literature supports this observation,2,3

no direct comparative data are relevant to cur-

rent practice. This study is based on a recent

cohort of patients with well-defined primary tu-

mor sites treated and followed-up with a uniform,

Correspondence to: J. O. Boyle

Presented at the 6th International Conference on Head and Neck Cancer,Washington, DC, August 8, 2004.

B 2005 Wiley Periodicals, Inc.

HEAD & NECK December 20051042 Second Primary Malignancy

multidisciplinary philosophy at a single institu-

tion. The objectives of this study were to identify

predictors and to compare the incidence and pat-

terns of SPM of the aerodigestive tract (SPMADT)

in patients with squamous cell carcinoma of the

oral cavity (SCCOC) and larynx (SCCL) treated

at a tertiary cancer care center.

PATIENTS AND METHODS

The study population of 1257 previously un-

treated patients was derived from two existing

databases at the Memorial Sloan-Kettering Can-

cer Center (MSKCC, New York, NY): 595 pa-

tients with SCCOC treated between 1986–1995

and 662 patients with SCCL treated between

1984–1998. The median follow-up period from

the date of treatment of the index primary tumor

was 73 months (range, 1–186 months) for SCCOC

and 60 months (range, 1–219 months) for SCCL.

There was no minimum follow-up limit to prevent

selection bias; however, all patients in the study

were followed a minimum of 5 years after treat-

ment at the time the data were collected.

Patient demographic data are shown in

Table 1. The median age at diagnosis of the index

tumor was 61 years (range, 14–94 years) for

SCCOC and 60 years (range, 22–93 years) for

SCCL. The two groups differed significantly in

terms of sex distribution and tobacco and alcohol

use. A higher proportion of patients with SCCL

were smokers compared with the SCCOC group,

whereas alcohol use was reported more fre-

quently among patients with SCCOC.

The index malignancies were classified as oral

or larynx and staged at diagnosis according to the

American Joint Committee on Cancer guidelines

(5th ed, 1997).4 All patients had histologically con-

firmed squamous cell carcinomas. Clinical TNM

staging data are displayed in Table 2. The clinical

T classification distribution in the SCCOC and

SCCL groups was as follows: 186 versus 173 T1,

235 versus 222 T2, 96 versus 179 T3, and 78 versus

88 T4. There were 966 patients with N0 disease

(473 SCCOC vs 493 SCCL), 150 patients with N1

disease (71 SCCOC vs 79 SCCL), 123 patients with

N2 disease (49 SCCOC vs 74 SCCL), and 18 pa-

tients with N3 disease (2 SCCOC vs 16 SCCL).

Treatment of the index primary tumor was

administered according to the guidelines of the

institutional multidisciplinary disease manage-

ment team. Single-modality treatment with sur-

gery was performed in 519 (41%) patients (360

SCCOC vs 159 SCCL), and postoperative adju-

vant radiation was performed in 359 (29%)

patients (235 SCCOC vs 124 SCCL). Primary

radiation was used to treat 229 (18%) patients

with SCCL; patients with SCCOC were not

treated with primary radiation. Organ-preserving

chemoradiation was used only for patients with

SCCL (n = 149).

Table 1. Patient characteristics.

Demographic information

No. of patients (%)

Fisher exact

test p value

SCCOC

(n = 595)

SCCL

(n = 662)

Age, y

V60 283 (48) 339 (51) 0.2

>60 312 (52) 323 (49)

Sex

Female 251 (42) 174 (26) .0001*

Male 344 (58) 488 (74)

Tobacco smoking (data

not available = 122)

No 88 (19) 44 (7) .0001*

Yes 388 (81) 615 (93)

Alcohol use (data not

available = 199)

No (including social

drinkers)

171 (43) 377 (57) .0001*

Yes 228 (57) 282 (43)

Tobacco and alcohol use

(no data = 199)

Never smoked, never

drank

69 (17) 25 (4) .0001*

Others 330 (83) 634 (96)

Abbreviations: SCCOC, squamous cell carcinoma of the oral cavity;SCCL, squamous cell carcinoma of the larynx.*Statistical significance.

Table 2. Comparison of clinical extent of tumor in patients with

SCCOC vs SCCL.

Tumor characteristics

No. of patients (%)

Fisher exact

test p value

SCCOC

(n = 595)

SCCL

(n = 662)

Clinical T classification

T1/T2 421 (71) 395 (60) .0001*

T3/T4 174 (29) 267 (40)

Clinical N classification

N0 473 (79) 493 (74) .01*

N1 71 (12) 79 (12)

N2/N3 51 (9) 90 (14)

Overall clinical stage

Stage I/II 376 (63) 337 (51) .0001*

Stage III/IV 219 (37) 325 (49)

Abbreviations: SCCOC, squamous cell carcinoma of the oral cavity;SCCL, squamous cell carcinoma of the larynx.*Statistical significance.

Second Primary Malignancy HEAD & NECK December 2005 1043

SPMs were defined by standard criteria: both

tumors were histologically malignant; two cancers

were geographically separate and distinct, ana-

tomically separated by normal mucosa (at least

2 cm); and the possibility that one tumor repre-

sented metastasis from the other was excluded.5

Tumors that developed within the anatomic

vicinity of the index tumor 5 years or more after

treatment of the index tumor were also classified

as SPMs. SPMs were further classified chronologi-

cally.6 The head and neck tumor that brought the

patient to examination was designated the index

primary tumor. Synchronous SPMs were diag-

nosed simultaneously or within 6 months of the

index tumor. Metachronous SPMs were diagnosed

6 months after index tumor diagnosis.

This study concerns patients who had a

SPMADT develop, defined as a second primary

neoplasm of the head and neck, esophagus, or

lung (Table 3). For this reason, a total of 47

patients with SPM development at other sites

were excluded from this analysis. In the SCCL

group, 12 patients were excluded for sites outside

the UADT (four prostate, three breast, two liver,

one cervix, one bladder, one colon), 12 for

cutaneous malignancies, four for more than one

site outside the UADT, three for lymphoma, and

two for thyroid neoplasms. In the SCCOC group,

three patients were excluded for cutaneous

carcinomas, two for more than one tumor outside

the UADT, and nine for SPM outside the UADT,

including prostate (n = 3), liver (n = 2), breast (n =

2), and bladder (n = 2).

All patients underwent a standard follow-up

schedule, consisting of a complete history and

detailed head and neck examination every 6 to

8 weeks during the first year, every 3 months

during the second year, every 6 months during

the third through fifth year, and every 6 months

to annually thereafter after completion of therapy

for the index primary tumor. Patients also

obtained annual chest radiographs and comple-

mentary investigations as necessary on the basis

of symptoms and clinical findings.

Statistical analyses were performed with a

commercially available computer software pack-

age (JMP 4.0; SAS Institute Inc., Cary, NC). The

primary endpoint of interest was development of

a SPMADT. The SPM-free interval was calcu-

lated in months from the date of index treatment

to the date of clinical or radiologic documenta-

tion of SPMADT. Patients who did not have

SPMADT develop during the observation period

were censored (n = 1140). Secondary endpoints

included 5-year overall survival (OS), 5-year

disease-specific survival, and 5-year recurrence-

free survival. The survival after SPMADT de-

velopment was calculated from the date of

diagnosis of the SPMADT to the date of the

last follow-up visit or the patient’s death.

SPMADT incidence and survival rates were cal-

culated by the Kaplan–Meier method. Univari-

ate comparisons between groups were performed

with the log-rank test. A p value of .05 or less

was considered statistically significant. Prog-

nostic factors that were significant on univari-

ate analysis were analyzed in Cox proportional

hazards models for independent significance.

Nonparametric qualitative and quantitative com-

parisons were performed with the Fisher exact or

Pearson chi-square tests and the Mann–Whitney

U test, respectively.

RESULTS

The 5-year incidence of SPMADT calculated by

the Kaplan–Meier method for all patients was 9%

(8% in the SCCL vs 10% in the SCCOC subgroup,

p = NS; median time to SPMADT development,

24 vs 41 months) (Figure 1). The 5-year incidence

rates for lung SPM were 5% for SCCL compared

with 3% for SCCOC ( p = .01). The 5-year

incidence rates for squamous cell carcinoma of

the head and neck (SCCHN) SPM development

Table 3. Summary of Sites of SPMADT by index primary site.

Primary tumor

No./% of column total/% of row total by site of SPMADT

Lung SCCHN More than one site Esophagus

SCCL primary (n = 51) 31/65%/61% 6/15%/12% 12/57%/24% 2/29%/4%

SCCOC primary (n = 66) 17/35%/26% 34/85%/52% 10/43%/15% 5/71%/8%

48 40 28 7

Abbreviations: SPMADT, second primary malignancy of the aerodigestive tract; SCCL, squamous cell carcinoma of the larynx; SCCOC, squamous cellcarcinoma of the oral cavity; SCCHN, squamous cell carcinoma of the head and neck.


were 2% for SCCL compared with 6% for SCCOC

( p < .0001).

Table 4 displays the factors analyzed for

SPMADT-free survival. Tobacco smoking and al-

cohol use were the only independent predictors

of SPMADT development. Smokers had a five-

fold increased risk (95% confidence interval [CI],

1.3–22; p = .02), whereas alcohol use was asso-

ciated with a twofold increased risk (95% CI, 1.4–

3.3; p = .02). Patients who never smoked tobacco

or used alcohol had a higher 5-year SPM-free

survival compared with other patients (98% vs

90%; p = .001).

The 5-year overall survival was 68%. Overall

survival was 65% for patients who had SPMADT

compared with 68% for those who did not ( p =

NS). The 5-year disease-specific survival was

81%, 94% for patients who had SPMADT com-

pared with 79% for those who did not ( p = .01).

The 5-year recurrence-free survival was 66%, 79%

for patients who had SPMADT compared with

65% for those who did not ( p = .02). A comparison

of survival rates for SPMADT chronicity revealed

that patients who had metachronous tumors

develop had a significantly higher 5-year overall

survival compared with patients who had syn-

FIGURE 1. Second primary malignancy of the aerodigestive tract

(SPMADT)– free survival rates in patients with primary squamouscell carcinoma of the oral cavity (SCCOC) and squamous cell car-

cinoma of the larynx (SCCL). [Color figure can be viewed in the

online issue, which is available at www.interscience.wiley.com.]

Table 4. Clinical predictors of SPM-free survival.

Factor No. of patients 5-y SPMFS, %

Univariate analysis,

log-rank test

Multivariate analysis, relative risk

(95% confidence limits), p value

Age, y

V60 622 93 .5

>60 635 88

Sex

Female 425 91 .4

Male 832 91

Tobacco smoking

No 132 98 .0003* Reference 5.2 (1.3–22); .02*

Yes 1003 90

Alcohol use

No (including social drinkers) 548 95 .0001* Reference 2.1 (1.4–3.3); .02*

Yes 510 87

Primary tumor site

Oral cavity 595 90 .09

Larynx 662 92

Clinical T classification

T1 359 94 .1

T2 457 92

T3 275 89

T4 166 85


N0 966 92 .003* NS

N1 150 85

N2 123 85

N3 18 100


N0 966 92 .001* NS

N+ 291 86

Abbreviations: SPM, second primary malignancy; SPMFS, second primary malignancy – free survival; NS, not significant.*Statistical significance.


chronous tumors develop (70% vs 45%, p = .003);

however, 5-year disease-specific survival (94% vs

94%, p = NS) and recurrence-free survival (79% vs

82%, p = .70) were not statistically significant

(Figure 2).

Patients were observed for 1 to 219 months

(median, 53 months) after diagnosis of the

SPMADT. The 2- and 5-year survival rates were

43% and 19% after diagnosis of SPMADT of the

lung compared with 77% and 66% for those of

the head and neck region ( p < .0001). The median

time to death for these groups was 14.5 months

and 23 months, respectively (Figure 3).

DISCUSSION

Head and neck cancer results from the accumu-

lated genetic changes from exposure to tobacco

carcinogens and the effects of alcohol over

decades. SPMs account for approximately a third

of head and neck cancer deaths, and a quarter of

patients followed for 10 years will have SPM

develop.1,2 It is, therefore, critical to understand

the patterns of occurrence and the risk factors for

SPM, to develop rational protocols for follow-up

screening and prevention strategies. In compar-

ing and contrasting the incidence and risk factors

for SPM in patients with either SCCOC or SCCL,

we have made some pertinent observations.

The site of head and neck primary carcinoma

predicts the site of SPM and, therefore, survival

from SPM. Patients with oral cancer tend to have

SPM develop in the head and neck region and

tend to have a better prognosis. On the other

hand, patients with laryngeal cancer tend to have

lung SPM develop and die of their disease.

Patients with SCCOC were more likely to report

alcohol use than the patients with SCCL. Ex-

posure to alcohol contributes primarily to carcino-

genesis in the oral cavity and pharynx and less so

in the larynx, which is consistent with the ex-

posure of these tissues to consumed alcohol. It is

likely that our finding of more frequent head and

neck SPM after SCCOC than SCCL is due to the

field effects of the combined exposure to tobacco

FIGURE 3. Survival rates after diagnosis of second primary

malignancy (SPM) of the lung and head and neck region.

FIGURE 2. Influence of second primary malignancy of the

aerodigestive tract (SPMADT) development on overall survival

(A), disease-specific survival (B), and recurrence-free survival

(C). [Color figure can be viewed in the online issue, which isavailable at www.interscience.wiley.com.]


and alcohol. The role of alcohol in carcinogenesis

remains enigmatic despite research in this area.

Alcohol may enhance tobacco carcinogens by in-

creasing their solubility, increasing mucosal cell

membrane permeability, causing inflammation,

or by direct carcinogenic effects. Understanding

this mechanism might help define strategies

specifically designed to reduce head and neck

SPM after oral cancer. Understanding the risk of

future head and neck SPM after SCCOC obviates

the necessity for detailed physical examination of

the head and neck at least yearly for life after

SCCOC. Topical liquid drug delivery might

effectively deliver chemopreventive agents to the

tissues at risk for SPM after SCCOC.

Conversely, primary laryngeal cancers are

caused by exposure to inhaled tobacco smoke.

Our finding that laryngeal cancer primary tumors

predict a higher proportion of SPM in the lung is

consistent with the hypothesis that these patients

demonstrate sensitivity to inhaled carcinogens.

Particulate matter in tobacco smoke that settles

in the glottis and bronchi may be of similar size

and composition. The embryologic origin of the

squamous mucosa of the glottis is related to that

of the bronchi; therefore, they share similar

biology and susceptibility to mutagens. The data

suggest that patients with SCCL with a history of

heavy smoking and a good prognosis may benefit

from intensifying the posttreatment screening for

lung cancer. Strategies may include more fre-

quent or more sensitive testing to downstage

lung SPM at diagnosis in the hope of improving

survival. Topical inhaled chemopreventive agents

may be efficacious in preventing SPM after SCCL.

Other authors have inconsistently identified

similar site specificity of SPM.2,3,7 – 10 These

studies are often hindered by small size, analysis

of too many head and neck primary sites, poorly

defined follow-up and screening, or long duration

over several decades of evolving treatment and

follow-up strategies. This study reviews a recent

cohort of patients with either laryngeal or oral

cancer treated at a single institution by a multi-

disciplinary team with a homogeneous philosophy

of treatment and follow-up.

The overall 5-year incidence rate of SPMADT

for our patients (10%) was not significantly dif-

ferent between the SCCL and SCCOC subgroups.

In contrast, the literature reports incidence rates

for SPMADT in patients with head and neck

cancer ranging from 9.4%3 to as high as 20.9%,11

and rates for patients with SCCOC tended to be

slightly higher than for patients with SCCL (9.6%

to 13% vs 6.6% to 9.9%).3,12 However, our data are

not directly comparable with those in the liter-

ature because of the use of different statistical

methods for calculating incidence rates and by the

time period of the studies.

In our experience, SPMADT occurred synchro-

nously more often in SCCL than in SCCOC (35%

vs 9%), and the median time to SPMADT was also

shorter for the SCCL subgroup than the SCCOC

subgroup. In contrast, the report from a commun-

ity-based registry by Gluckman et al12 found that

synchronous SPMADT was more common in

SCCOC than in SCCL (87 of 201 or 43% vs 63 of

211 or 30%).

Our data (Figure 2) indicate that the 5-year

overall survival rate in patients who had

SPMADT develop was similar to those who did

not. Furthermore, patients with SPMADT had

significantly improved 5-year disease-specific

survival and 5-year recurrence-free survival

rates. These observations support the logic that

patients with improved survival after treatment

of their primary tumor have greater opportunity

for metachronous tumor development. As re-

ported by other authors,2,7,13,14 survival after

diagnosis of SPM of the lung was significantly

poorer in our patients than survival after SPM of

the head and neck region.

Smoking tobacco and alcohol use were the only

independent predictors of SPMADT, and more

patients with SCCL were smokers, whereas more

patients with SCCOC used alcohol. This strength-

ens the association between carcinogen exposure

and pattern of SPM development.2,13–15 Our

analyses show that smokers had a fivefold

increased risk of SPMADT development, whereas

alcohol use was associated with a twofold in-

creased risk of SPMADT development. The retro-

spective nature of this study introduces several

limitations to our data, including the subjec-

tive nature of the degree of tobacco and alcohol

use, duration of use, and the continued use of

tobacco and alcohol after treatment that may be

more likely to contribute to SPMADT develop-

ment than the initial history. It is controversial

whether smoking cessation lowers the risk of SPM

development; studies have reported a decreased

risk of SPM in patients who stopped smoking

after tumor diagnosis,16–18 and others have not

found this to be true.19,20

We have identified two distinct populations of

patients with SCCHN in terms of risk of

SPMADT development. The observations out-

lined previously have a practical implication in


designing post-therapy surveillance protocols. Pa-

tients with laryngeal cancer, especially smokers,

are at an increased risk of lung SPM and may

benefit from more aggressive chest screening.

Patients with oral cancer may benefit the most

from lifelong annual physical examination to

identify early SPMADT. However, these findings

do not preclude the necessity of at minimum a

yearly physical examination and chest radiograph

for all patients with head and neck cancer at any

site, particularly for smokers. Our uniform policy

of recommending frequent physical examination

and annual chest radiographs may have yielded

benefit. Nonsmokers seem to have a much lower

risk of second primary lung cancers. Our data

suggest that regular screening for lung SPM may

be more cost-effective in patients who have had

treatment for SCCL, especially those whose

tumors are associated with smoking tobacco.

The importance of our findings lies in the fact

that we quantify the relative risk of SPMADT

developing after treatment of two of the most

common squamous cell carcinomas of the head

and neck. Understanding patterns, outcomes, and

risk factors of SPM may assist in the design of

screening and preventive interventions in head

and neck squamous cell carcinoma.

SUMMARY

The incidence of SPMADT in patients treated for

SCCOC is comparable to that in patients treated

for SCCL, but the patterns of SPMADT are

different in these two subgroups. SPM of the lung

is more common in the SCCL group and is

associated with poor survival, whereas SPM of

the head and neck is more common in the SCCOC

group and has a better outcome. Tobacco smoking

and alcohol use are independent predictors for the

development of SPMADT in patients treated for

SCCOC and SCCL.

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