Second Malignant Neoplasms in Head & Neck Cancer Patients

Acla Oncologica Vol. 32, No. 3, pp. 283-288, 1993
SECOND MALIGNANT NEOPLASMS IN PATIENTS WITH HEAD AND NECK
SQUAMOUS CELL CARCINOMAS
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MORTENBOYSENand JENSOYVINDLOVEN
The incidence of second malignant neoplasms (SMN) was analyzed in 714 patients with squamous
cell carcinomas of the oral cavity, oropharynx, hypopharynx and larynx. With a minimum follow-up of
3.5 years and 2 540 person-years at risk 84 S M N (10 synchronous and 74 metachronous) developed in
81 patients. The relative risk of S M N was 2.4. The actuarial method showed an annual incidence of
SMN of 3.5%. For oral cavity and oropharyngeal tumors the annual incidence of SMN was 4.0% and
3.8% respectively, compared to 2.10/0 for laryngeal cancer (p < 0.013 and 0.017 respectively). Sex, age
or stage of the index tumor did not significantly influence the annual incidence of SMN. After 3 years
of follow-up, SMN became more a cause of concern than loco-regional relapse.
-
Patients treated for carcinoma of the head and neck are
more liable to develop second malignant neoplasms
(SMN) than can be explained by chance alone ( I ) . The
reported crude rate of SMN ranges from 3.8 to 33% (2, 3).
This wide range incidence may partly be explained by the
site of the index tumour, type of treatment, ethnic and
racial differences, increased life expectancy and partly by
the increasing awareness of such tumors, more thorough
evaluation, and improved survival rates. The cumulative
incidence of SMN of course increases with the time the
patients have been observed. Crude rates below 11'% have
been reported in materials with a relative short (less than
4 years) observation time (4, 5 ) , while higher rates were
found in studies with longer observation time (2, 6-10).
Consequently, the percentage of SMN in relation to the
total number of patients treated Is misleading and of little
value for comparison of indices in different studies. The
actuarial method is more adequate for estimation of SMN
rates since it allows for correction of deaths from other
causes than SMN ( 1 1) and also accounts for the time the
patients have been under observation.
Received 22 May 1992.
Accepted 25 January 1993.
From the Department of Otolaryngology. National Hospital,
University of Oslo, Oslo, Norway (both authors).
Correspondence to: Dr Morten Boysen. Department of Otolaryngology, National Hospital. N-0027 Oslo I . Norway.
Since 1983, we have prospectively recorded relevant
clinical data and outcome of follow-up examinations of all
patients treated for carcinoma of the head and neck. By
applying the actuarial method we attempted to answer the
following questions: I ) How often does SMN occur? 2) Are
all groups of patients at equal risk of developing SMN? 3)
Does the site or stage of the index tumor influence the
incidence of SMN? 4) Where does SMN occur? 5) To what
extent does SMN influence the subsequent survival?
Material and Methods
During the 5-year period May 1983 to May 1988, 714
patients with histologically verified squamous cell carcinoma of the oral cavity, oropharynx. hypopharynx, and
larynx were treated at the Department of Otolaryngology,
National Hospital, Oslo, Norway. This material covers the
majority of patients with head and neck carcinomas in the
southern part of the country, diagnosed within the time-period in question. The clinical findings, treatment, results,
and outcome of all follow-up examinations have been
recorded prospectively. The material includes 69 patients
with previous malignant diseases. of which 35 were located
within the head and neck region. There were 168 (23.5%)
females and 546 (76.5%) males. The mean age was 64 years
(range 28-87). Sixty percent of the patients were in the
sixth decade of age with equal proportions above and below
this age grouping.
283
284
M . BOYSEN A N D J 0 LOVEN
Table 1
Clinical staging ofthe primary rumor according to site (UICC 1983)
Stage
Oral
cavity
Oro-
pharynx
6
Hypopharynx
Larynx
Total
102
63
38
99
167
I47
106
294
302
714
I
I1
111
IV
56
64
31
106
23
51
3
5
14
38
Total
257
95
60
15
death from any cause. Survival intervals were calculated
from the date of the diagnosis of the index tumor, with
the exception for the actuarial survival interval for the
SMN population which was calculated from the date of
the SMN diagnosis. The method of Kaplan-Meier was
used to determine the probability (actuarial risk) of developing SMN and survival. The log-rank method was
used for testing differences in survival and occurrence of
SMN (14).
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Results
The clinical examination was, when necessary for
evaluation of the extent of the tumor, supplemented by
palpation under general anesthesia and endoscopic examinations. CT examination of the primary tumor and the
neck as well as chest radiographs were performed in all
patients. Bronchoscopy and esophagoscopy were only performed when symtpoms or chest radiographs raised suspicion of disease in these organs. Table 1 presents the staging
according to the 1983 UICC staging system (12). In general, the smaller tumors, Tl-2, received radiotherapy with
surgery for suspected residual tumor and the larger ones
combined radiotherapy and surgery.
The patients were followed with 2-3 months’ intervals
for the first two years, and every three to four months the
following years. Panendoscopic and chest radiographs
were not compulsory parts of the examination and only
performed when some abnormality necessitated further
evaluation. Apart from the site and date of SMN we noted
how the SMN was diagnosed; 1) through the clinical
examination alone at scheduled routine follow-up consultations or 2) through symptoms reported by the patients at
the scheduled consultations or at interval visits requested
by the patients. The minimum follow-up was 3.5 years.
None of the patients were lost to follow-up. The data were
analyzed as of 1 December, 1991. Hospital records were
obtained in all cases of new malignancies. For deceased
patients death certificates were obtained and autopsy
records were reviewed when available.
The criteria proposed by Warran & Gates ( 13) were used
to identify additional primary malignancies; namely 1) both
tumors have to be malignant at histological examination,
2) the tumors have to be separated by normal non-neoplastic tissue, and 3) the possibility that the second tumor
is a metastasis of the first has to be eliminated. Skin tumors
were not included. If a second malignant neoplasm was
diagnosed simultaneously o r within a period of 6 months
from the diagnosis of the index tumor, the secondary
tumor was considered synchronous. Malignancies diagnosed after 6 months were considered as metachronous.
The SAS (Statistical Analysis System) 6.03 software for
personal computers (SAS Institute Inc., Cary, NC, USA)
was used for storage, processing and data evaluation. The
statistical endpoints were either occurrence of S M N or
A total of 84 SMN developed in 81 (3 with 2 SMN) of
the 714 patients (Table 2) during 2 540 person-years at
risk. The expected number of malignancies on the basis of
rates prevailing in the general population was 35, resulting
in a relative risk ( R R ) of 2.4 (females RR = 2.6 and males
RR = 2.4). Ten SMN (12%) were synchronous and 74
(88%)) metachronous. Table 2 shows that 58 (69%) of the
SMN were located within the head and neck, lungs and
esophagus. Of the 35 patients who had had a malignant
tumor within the head and neck before 1983, 4 developed
an additional malignant disease. These tumors were in fact
third malignant neoplasms, but for the present analysis
they were considered as SMN. Fourteen (17%) of the
S M N (mainly those situated within the head and neck
region) were detected through the clinical examination at
routine follow-up consultations, the rest being diagnosed
through symptoms presented by the patients either at
routine follow-up o r at interval consultations requested by
the patients.
Overall, the average annual risk of developing SMN in
an 8-year follow-up period was 3.5% (Fig. 1). Compared
to laryngeal carcinomas (2/3 were glottic carcinomas) Ordl
cavity and oropharyngeal index tumors had a significantly
Table 2
Number and sites of second malignant neoplasms ( S M N ) in 714 parienrs wirh squamous cell carcinomas
of the oral cavity, mesopharynx,
hypopharynx and larynx
Site
SMN*
(%)
n
~~
Head and neck
Lung
Oesophagus
Abdominal
29
19
10
Other
22
4
Total
84
(35)
(22)
(12)
(26)
(5)
* Three patients had 2 second malignant neoplasms
285
SECOND MALIGNANT NEOPLASMS IN HEAD A N D NECK CARCINOMAS
.oo
1
1.o
,, ,
\.
0.96
P
P
R 0.90
R
0
0
B
A
B
0.85
B
\
]
L
I
T
y
->
-.
0
A
,
0.0
0.8
L
I
T
Y
0.80
L
0.7
Female
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0.76
0.70
0.6
o
i
2
3
4
6
e
7
e
e
10
0
YEARS
1
2
3
4
6
6
7
8
9
10
Y€AR3
Fig. I . The probability of being free of a second malignant
neoplasm for 714 patients with squarnous cell carcinoma of the
oral cavity, oropharynx, hypopharynx and larynx.
Fig. 3. The probability of being free of a second malignant
neoplasm according to sex.
higher annual rate of SMN (2.1% vz 4.0% and 3.8%
respectively: p = 0.013 and 0.017). When comparing laryngeal and hypopharyngeal carcinomas no significant difference in the incidence of SMN was found (Fig. 2). Sex (Fig.
3), age (Fig. 4) or stage (Fig. 5 ) did not influence the
incidence of SMN significantly. Patients developing SMN
had a statistical significant ( p < 0.01) lower survival when
compared to those who did not develop SMN (Fig. 6).
Death rates due to SMN at 3, 5 and 8 years were 2.8, 5.5
and 7.1% respectively (Fig. 7). Among the deceased patients, SMN was the cause of death in 9.8% and 11.5% and
5 and 8 years' follow-up respectively.
0.0
I
0
I
1
2
3
4
6
6
7
8
9
10
Ytma
Fig. 2. The probability of being free of a second malignant
neoplasm according to the site of the primary tumor. (Log-rank
statistics: laryngx vs. oral cavity p = 0.013, laryngx vs.
oropharyngx p = 0.017, laryngx vs. hypopharyngx n.s.).
286
M .BOYSEN AND I. 0.LOVEN
%
.......
.....
P
0.0
36.9 PT
!I
B
A
8
I 0.0
L
2ol T 7"
I
7
Stage I + 11
I
T
!:
1.
................
Y
0'
Stage III+ IV
I
38.3 ANED
c
c
4
3
5
8 YEARS
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Fig. 7. Schematic presentation of the percentage of patients alive
(lower curve), deaths from second malignant tumors (SMN),
deaths from non-malignant diseases (NMD), and deaths due the
primary tumor (PT) at 3, 5 and 8 years after initiation of
treatment of the primary tumor.
0.8
0
1
2
3
A
6
6
7
8
0
10
YEAR3
Fig. 5. The probability of being free of a second malignant
neoplasm according to the stage of the primary tumor.
1.o
0.8
P
R
0
0 0.e
A
B
I
L
I
0.4
Y
0.2
0.c
O
1
2
3
4
6
8
7
6
9
I0
YE4RS
Fig. 6. The absolute survival for patients who did not develop a
second malignant neoplasm (no SMN), calculated from the date
of the index tumor diagnosis and those who did develop SMN
(with SMN), calculated from the date of SMN diagnosis
( p < 0.01).
Discussion
The incidence of second malignant neoplasms is usually
presented as a percentage of the number of patients initially treated. However, the crude rate of SMN represents
an underestimate of the risk for the patient who survives,
since patients die from the index tumor and intercurrent
diseases before a secondary carcinoma can develop ( 11).
Crude rates neither take the period of follow-up into
consideration. The actuarial method of calculating the risk
of SMN gives a better estimate since it allows for correction of causes of death other than deaths due to SMN.
In accordance with others studies (3, 11, 15-17) we
found that SMN develops at a steady annual rate. Disregarding the site of the index tumor the present study
showed an annual incidence of SMN of 3.5% during 8
years. SMN will continue to develop ( 5 , 8, 9, 18), possibly
at the same rate, for more than 10 years (3). An overall
annual rate of 3.5% is similar to that found by Cooper et
al. (15), but considerably less than the rate of 6% found by
Vikram et al. (19). SMN seems to appear at a significantly
lower rate for patients with laryngeal tumors compared to
patients with oral and pharyngeal index tumors ( 5 , 20). It
has furthermore been reported that supraglottic carcinomas have a three-fold higher incidence of SMN than
glottic carcinomas (17). The majority of the laryngeal
carcinomas in the present study were glottic, and the lower
rate of SMN, found in the present material, might thus be
explained by the high percentage of glottic carcinomas.
For oral cavity index tumors we found an incidence of
SMN of 4%, i.e. rather similar to the incidence of 3.6%
reported by Tepperman & Fritzpatrick (3).
In the present study age or sex of the patients or stage of
the index tumor did not seem to influence the incidence of
SMN. Some other authors (10, 21), however, have reported higher incidence of SMN in males both for oral and
laryngeal carcinomas. As to the influence of the stage of
the index tumors conflicting results have been presented.
Some (16) have observed a higher rate in patients with
T3/T4 laryngeal tumors compared to T1/T2 laryngeal
carcinomas, while others (18) found the opposite to be
the case.
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SECOND MALIGNANT NEOPLASMS IN HEAD A N D NECK CARCINOMAS
At 5 years’ follow-up 18% of our patients who still were
alive had developed SMN and these tumors were responsible for 10% of the total number of deaths. Relapse of head
and neck cancer usually becomes manifest within 3 years
(22). Thus, for patients whose index tumor was under
control at 3 years, SMN had become an equal and at 5
years a more pronounced cause of concern than loco-regional o r distant relapse of the index tumor (Fig. 6).
Somewhat paradoxically this is of particular importance to
patients with early stage tumors who most likely survive
the index tumor (7, 9, 15). If some type of screening for or
preventive measures of SMN should be recommended, it is
for this group of patients.
Our finding that two-thirds of the SMN occurred within
the head and neck region, esophagus and lungs corresponds to previous studies (5, 18, 20, 23). This high
percentage clearly reflects the concept of field cancerization
(24, 25) and focuses on early diagnosis and preventation of
such tumors. During the last years several prospective and
retrospective studies have been published in which panendoscopy was used in the initial evaluation. These studies
show rates of simultaneously or synchronously occurring
carcinomas in head and neck patients ranging from 6 to
14% (26-30). Approximately half of these tumors would
not have been detected without panendoscopy (31). The
head and neck region seems to be the most frequent site of
the simultaneously occurring tumors, followed by
esophageal and lung tumors (6, 27, 31, 32). Most studies
not including panendoscopy in the initial work-up show an
incidence of synchronously occurring carcinomas of only
1-2% (8, 21, 28, 32). It is reasonable to assume that many
undetected simultaneous or synchronous lesions within the
head and neck region have been cured by the extensive use
of wide-field irradiation of the index tumor. SMN arising
outside the irradiated field, such as tumors of the lungs
and esophagus will. on the other hand, continue to progress and are not diagnosed until they cause clinical
symptoms.
Early diagnosis of simultaneous carcinomas is an appealing concept, but due to the poor prognosis of these
tumors there are only a few studies suggesting that early
detection of SMN in fact increases the survival (31, 34).
The most important consequence of early diagnosis of
synchronous bronchial and esophageal tumors would
probably be that their detection might influence the treatment of the index tumor.
Whether screening for bronchial carcinomas should be
performed at regular intervals during follow-up after treatment of the index tumor is still a matter of controversy. In
an attempt to clarify the role of endoscopic and sputum
cytology during follow-up an extensive multicenter screening program was designed in Europe (Euroscan). The
screening arm was, however, recently omitted ( I ) . In the
present study 4 of the 19 patients with bronchial carcinoma are alive ( 2 with residual SMN) but none of the 8
287
patients with esophageal carcinoma. It is still an unanswered question whether the possible benefit of regular
endoscopic examinations really justifies the costs and
efforts.
Twenty-nine of the 84 SMN in the present material were
located within the head and neck region and the majority
of these occurred within previously irradiated regions. The
steady annual rate of SMN and the relative short observation
time agrees with previous reports (35, 36) suggesting that
radiotherapy, if any, plays a minor role in the etiology of
secondary carcinomas of the head and neck. There is
convincing epidemiological evidence to implicate tobacco as
the foremost carcinogen in the upper aerodigestive tract
and lungs. Alcohol, on the other hand, appears to act as
a promotor (1). Unfortunately it is not confirmed, but
cessation of smoking and limitations in the intake of
alcohol might reduce the incidence of SMN (37). Retinoids
may prevent developments of SMN and trials designed
to answer this important question are currently in progress
(1, 16).
Most studies on SMN consist of hospital record reviews
and d o not take into account SMN in patients lost to
follow-up or those who continue to be treated elsewhere.
This may cause under-reporting of SMN, in particular of
those occurring outside the head and neck. To obtain a
more true incidence of SMN all patients should be followed closely for a certain period of time. There is also a
need for a more standardized way of presenting the incidence of secondary malignancies. The actuarial method
satisfies this demand. This method also makes it possible
to compare rates for different sites of index tumor, tumor
stage, and sex and also t o compare different studies.
ACKNOWLEDGEMENTS
This study was supported by the Norwegian Cancer Registry.
We also wish to thank A. Andersen at the Norwegian Cancer
Registry for calculations of the relative risks and advices concerning the presentation.
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