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ORIGINAL ARTICLE
ONCOLOGIC OUTCOMES IN ADVANCED LARYNGEAL
SQUAMOUS CELL CARCINOMAS TREATED WITH DIFFERENT
MODALITIES IN A SINGLE INSTITUTION: A RETROSPECTIVE
ANALYSIS OF 65 CASES
Francesco Bussu, MD, PhD,1 Francesco Miccichè, MD,2 Mario Rigante, MD, PhD,1
Nicola Dinapoli, MD,2 Claudio Parrilla, MD, PhD,1 Pierluigi Bonomo, MD,2 Gabriella Cadoni, MD,1
Giovanna Mantini, MD,2 Jacopo Galli, MD,1 Vittoria Rufini, MD,3 Giovanni Almadori, MD,1
Vincenzo Valentini, MD,2 Gaetano Paludetti, MD1
1
Institute of Otorhinolaryngology, Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy.
E-mail: [email protected]
2
Institute of Radiotherapy, Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
3
Institute of Nuclear Medicine, Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
Accepted 16 February 2011
Published online 20 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21785
Abstract: Background. Treatment for laryngeal squamous
cell carcinoma (SCC) has been predominantly surgical for
decades, but in the last 20 years nonsurgical modalities (radiotherapy), with the aim of organ preservation, also became
predominant among advanced stages. Retrospectively evaluating our series of stage III and stage IV laryngeal SCCs, we
compared the 2 main therapeutic modalities.
Methods. Medical records of 65 consecutive patients with
advanced laryngeal SCC, from November 2005 to January
2009, were reviewed.
Results. Among irradiated patients 2-year organ preservation was 86% for cT2, 43% for cT3, and 17% for cT4a (p ¼
.037, Wilcoxon test). With respect to survival, the only significant differences between surgery and radiotherapy were
detected among cT4a SCCs (p ¼ .03, Wilcoxon test), in favor
of surgery.
Conclusions. The present results confirm the surgical recommendation for cT4a laryngeal SCCs. On the other hand, for
T < 4, our results confirm that radiochemotherapy warrants a
survival similar to that of total laryngectomy, thus allowing us to
C 2011
preserve the larynx in a relevant number of cases. V
Wiley Periodicals, Inc. Head Neck 34: 573–579, 2012
Keywords: advanced laryngeal cancer; radiotherapy; surgery;
multidisciplinary approach; head and neck oncology
Although the larynx is considered a site of the head
and neck, studying laryngeal malignancies separately
has a rational basis because several peculiarities,
from both clinical and molecular perspectives, can be
highlighted. The American Cancer Society classifies
larynx as a part of the respiratory system, separately
from the oral cavity and pharynx.1 With respect to
Correspondence to: F. Bussu
C 2011 Wiley Periodicals, Inc.
V
Surgery vs CTRT in Advanced Laryngeal SCC
the incidence, the male/female ratio is markedly
higher than that in other sites of the head and neck.
Differences in chromosomal and mutational pattern
and carcinogenic progression between laryngeal squamous cell carcinomas (SCCs) and the other head and
neck squamous cell carcinomas (HNSCCs) have been
detected by comparative genomic studies.2,3
Laryngeal SCCs represent the vast majority
(approximately 96%) of laryngeal malignancies.4 In
the United States, laryngeal SCC is estimated to
account for almost 1% of all new cases of malignancy,
with an incidence of about 10,000 cases per year, and
to cause 0.7% of all cancer deaths in 2009.1 Most of
these tumors originate in the glottis (>60%) and in
the supraglottis, whereas the subglottis is an
extremely rare site of origin (<5%).4
In accord with the most recent data by the American Cancer Society, 5-year disease-specific survival
(DSS) for laryngeal cancer is about 65%.1
Undoubtedly such a rate is widely affected by
various clinical and biological factors. The most important clinical factors are TNM classification at diagnosis, subsite of origin of the neoplasm within the
larynx (supraglottic, glottis, subglottic), primary
treatment modality, comorbidities, and both environmental and behavioral aspects (such as drinking
and smoking habits, which sometimes do not change
after diagnosis and treatment of a malignant
tumor).
Prognostic differences between glottic and supraglottic SCCs are well known: the 5-year overall survival (OS) rate was 77% for the former and 51% for
the latter. A first explanation of such a difference is
certainly the stage at diagnosis: 53% of glottic SCCs
are diagnosed in stage I, 22% in stage II, 23% in
stage III, and only 2% in stage IV (whose incidence at
HEAD & NECK—DOI 10.1002/hed
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573
diagnosis is probably increasing in the last few
years); on the other hand, only 9% of supraglottic
SCCs are diagnosed in stage I and 70% come to clinical observation in stage III or stage IV. Nevertheless,
prognosis of glottic cancer is also better within the
same stage of disease, especially in early cases: early
glottic cancer (stages I and II) has a 5-year OS rate
of about 90%, whereas early supraglottic cancer has
a 5-year OS rate of about 80%. Such a difference in
prognosis is mainly attributed to a higher regional
recurrence rate (nodal metastasis) for supraglottic
SCCs. This is secondary to a lower degree of differentiation and keratinization, to anatomic factors (such
as the rich lymphatic network of the supraglottic
region of the larynx), and to a less favorable biological profile.5
Despite the evident technical, technologic, and
methodologic advances of head and neck oncology in
the past 30 years, the prognosis of laryngeal SCC
did not demonstrate any improvement. In fact, the
documented 24.5% reduction in mortality rate from
1990 to 2004 is exclusively ascribed to the
decreased incidence that, in turn, is a result of the
primary prevention of and the campaign against
cigarette smoking in the United States.1 On the
other hand, the 5-year OS rate of laryngeal cancer
in the United States decreased from 67% in 1977 to
64% in 2004, and it remains, together with the adenocarcinoma of the uterine body, the only major
human cancer without a significant improvement of
survival in the past 30 years. These data are even
more striking if compared with data reported for
oral SCC, which increased from a 53% to a 60%
5-year survival rate in the same period.1 Advanced
stage is associated with a higher rate of relapse
and disease-related death, and the number of
advanced (especially stage IV) cases at diagnosis
seems to be increasing, especially for the supraglottis.4 For this reason the improvement of survival in
advanced cases (stages III and IV) would have the
most decisive impact on the overall prognosis of
laryngeal cancer.
In our institution the approach to laryngeal SCC
has been predominantly surgical for decades. In the
last 5 years, following international trends and in
the light of evidence of literature, it became multidisciplinary in every phase of management, from
diagnosis, to treatment, to follow-up, even in the
case of treatment failure. This setting allowed us to
manage an archive of uniformly staged patients,
with an accurate radiologic and clinical follow-up,
who underwent different radiotherapeutic and surgical treatment modalities. The purpose of the present
report was to retrospectively evaluate the oncologic
outcome of our series of advanced (stages III and IV)
laryngeal SCCs, to identify the major clinical predictive factors, and to compare the different therapeutic modalities in the above-cited multidisciplinary
setting.
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Surgery vs CTRT in Advanced Laryngeal SCC
MATERIALS AND METHODS
The medical records of 65 consecutive
patients diagnosed with advanced (stages III and IV)
laryngeal SCC at the Catholic University of Rome–
Policlinico Agostino Gemelli, from November 2005 to
January 2009, were reviewed to evaluate the outcomes and to compare the different therapeutic
modalities. Patients were excluded who (1) had a history of prior treatment for head and neck cancer,
known distant metastatic disease, nonsquamous neoplasms, who were not eligible for treatment with a
radical intent, or (2) did not undergo follow-up.
Patient characteristics included sex, Karnofsky Performance Status (KPS), and age at diagnosis. KPS
was determined based on each patient’s reported condition at the initial consult if one was not recorded in
the chart. Tumor characteristics included primary
site (glottis or supraglottic) and subsite, T and N classifications, and American Joint Committee on Cancer/
Union Internationale Contre le Cancer (AJCC/UICC)
stage. All the authors of the present report state that
the study was approved by their institution, Università Cattolica del Sacro Cuore–Policlinico Agostino
Gemelli, and that every patient gave written
informed consent for the treatment of data regarding
his/her pathology.
Selection of primary treatment modality in our
multidisciplinary setting was based mainly on cT classification and on patients’ general conditions and
preferences. That is, we irradiated cT2 and we recommended the operation in cT4 cases; cT3 cases were
discussed in the tumor board and underwent surgery
(mainly total laryngectomy, but also a partial operation in 4 cases), or radiotherapy, depending on
patients’ general conditions and preferences. Among
the patients who underwent primarily radiochemotherapy, there were also patients classified as cT4
who refused the recommended total laryngectomy
and preferred to try to keep their larynx, after having
been informed about the lower survival rates reported
in the literature.
Guided by the aim of obtaining information about
the adequacy of treatment in the different settings, we
grouped the cases based on the classification and the
nodal status in 3 groups: the first including all stage
III cases, the second including all N2 and N3 cases
(regionally advanced cases), and the third composed of
T4aN0–1 cases (locally advanced cases) (Table 1).
Patients.
Surgery. Among patients primarily treated by surgery, the primary tumor was treated by a partial or
total laryngectomy. Elective selective neck dissection
was performed in cN0 patients at risk for nodal metastases, with removal of levels II–IV in accord with
the main international guidelines.6 Comprehensive
neck dissection was performed for clinically positive
nodal disease.
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Table 1. Characteristics of patients in accord with the primary
treatment group.
Characteristic
Age, y
Median
Range
Sex
Male
Female
KPS
100
90
80
70
60
Site of primary
Supraglottis
Glottis
AJCC stage
III
IV
Locally advanced (cT4N0–1)
Regionally advanced (TxN2-3)
T classification
T2
T3
T4a
N classification
N0
N1
N2A
N2B
N2C
N3
Surgery
(n ¼ 30)
69
46–80
Radiotherapy
(n ¼ 35)
65
41–85
25 (83.3)
5 (16.7)
31 (88.6)
4 (11.5)
10
8
5
7
0
9
15
5
5
1
(33.3)
(26.7)
(16.7)
(23.3)
(25.7)
(42.9)
(14.3)
(14.3)
(2.8)
23 (76.7)
7 (23.3)
25 (71.4)
10 (28.6)
12
18
10
8
14
21
6
15
(40.0)
(60.0)
(33.0)
(27.0)
(40.0)
(60.0)
(17.0)
(43.0)
0
16 (53.3)
14 (46.7)
7 (20.0)
18 (51.4)
10 (28.6)
21
1
0
3
5
0
13
7
1
7
7
0
(70.0)
(3.3)
(10.0)
(16.7)
(37.1)
(20.0)
(2.9)
(20.0)
(20.0)
Abbreviations: KPS, Karnofsky Performance Status; AJCC, American Joint Committee on Cancer.
Note: Values represent number (%), except as otherwise noted.
Chemoradiotherapy. Postoperative radiation (XRT)
was administered for N2–N3 disease, extracapsular
spread, and adverse pathologic primary site features
including T4 disease, perineural invasion, involvement of surgical margins, or lymphovascular invasion. In the radiotherapy group, concomitant
chemoradiation with cisplatin, in accord with the protocol described by Forastiere and Adelstein,7,8 or
altered fractionation radiotherapy (hyperfractionated
RT or concomitant boost RT) in combination with
cetuximab was administered. We recorded as treatment parameters use of cetuximab or platinum-based
chemotherapy, duration, dose, and fractionation of
radiotherapy.
Outcome Analysis. Follow-up was calculated from
the start of radiotherapy or from the date of surgery.
Total laryngectomy was performed as salvage for
patients without a complete response to radiotherapy
or who developed recurrence. Patients with the suspicion of persistent nodal disease (especially cN2 and
cN3 cases) following radiotherapy underwent posttreatment comprehensive neck dissection. Primary
Surgery vs CTRT in Advanced Laryngeal SCC
endpoints included locoregional control (LRC), OS,
DSS, and distant metastasis-free survival (DMFS).
Differences among survival curves were always evaluated by Wilcoxon test. Differences in the distribution
of nominal variables among groups were evaluated by
chi-square test. All statistical analyses, including the
evaluation of survival and recurrence, were performed using JMP 7.0.1 software (SAS Institute,
Cary, NC).
RESULTS
Median follow-up in our group was 20 months; thus,
most of the following survival rates will be given at 2
years. Median age in the whole group was 65 years
(range, 41–85 years). Age and other clinical parameters in the 2 treatment groups are shown in Table 1.
Surgical procedure on T was total laryngectomy in
26 cases (87%), endoscopic laser cordectomy in 2
cases, endoscopic horizontal supraglottic laryngectomy (EHSL) in 1 case, and cricohyoidopexy in 1 case.
Thirteen patients (20%) in the present series developed 15 other primaries, 9 in the lungs (60%), 2 in
the larynx (with at least 8 years between the first
and the second primary), 2 in the breast, 1 in the
esophagus, and 1 in the colon. We recorded 15 deaths
in our series, 11 for laryngeal cancer, 2 for other primary malignancies, and 2 for other causes. We had 6
cases of distant metastasis (2 in surgical patients, 4
in irradiated patients), 5 in the lungs, 1 in the bones,
4 cases with recurrent disease, and 2 cases with
no locoregional disease. The OS rate in the whole
group was 73%, and the DSS rate was 82% at 2 years
(Figure 1).
When considering clinical parameters in the whole
group, we did not find any single clinical parameter
(T and N classifications, age, sex) influencing in a statistically significant extent the survival, statistically
significant differences in survival among stage III
cases, regionally advanced cases (N2–N3), and locally
advanced cases (T4N0–1), probably because of the
small sample; nevertheless, we observed a trend for a
worse long-term OS rate among cN2–3 stage IV (54%
at 4 years) than that among cT4N0–1 cases (74% at 4
years; but p ¼ .52, Wilcoxon test, in a comparison of
the 2 survival curves).
From the comparison between the group of the
primarily operated with the primarily irradiated
patients, no statistically significant differences
emerged as for OS (84% vs 64% at 2 years; p ¼ .31,
Wilcoxon test) and DSS (84% vs 80% at 2 years; p ¼
.95, Wilcoxon test) (Figure 2).
Organ-preservation rate in the radiotherapy
group was 45% in the whole group, including cT4 for
cartilage through invasion. When considering cT, the
organ-preservation rate at 2 years is 86% for cT2,
43% for cT3, and 17% for cT4a (Figure 3), with a statistically significant difference (p ¼ .037, Wilcoxon
test).
HEAD & NECK—DOI 10.1002/hed
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575
FIGURE 1. Overall survival (OS, A) and disease-specific survival (DSS, B) in the whole group of 65 laryngeal squamous
cell carcinomas (SCCs).
FIGURE 2. Comparison between the group of the primarily
operated (in blue) and the primarily irradiated (in red) patients
as for OS (A) and DSS (B).
With respect to OS and DSS, the only statistically
significant differences between surgery and radiotherapy were detected among cT4a, with an OS (DSS)
rate of 100% versus 60%, respectively, at 2 years (p ¼
.03, Wilcoxon test) (Figure 4). Nevertheless, notably,
if we exclude cT4 cases, we observe a better 2-year
OS rate among patients with positive node at diagnosis who underwent radiotherapy (73%), compared
with surgery (50%), but such a difference lacks statistical significance (p ¼ .2, Wilcoxon test) (Figure 5).
On the contrary, the 2-year OS rate of cT3N0 cases is
better in the surgical group (75% vs 45%) (Figure 5),
but also in this case the difference is not statistically
significant (p ¼ .27, Wilcoxon test).
than with almost any other malignancy. In fact, at
present, swallowing, phonation, breathing, and aesthetic appearance of a patient treated for laryngeal
cancer are critically relevant endpoints. This led
to the emergence of conservative strategies, both
DISCUSSION
In the past, treatment of laryngeal SCC focused
predominantly on cure by comprehensive surgery,
and all cT3 and cT4 cases underwent a total laryngectomy. Today, more than ever before, in clinical oncology a premium is placed on returning the patient
to a productive and useful lifestyle (ie, quality of life
after cancer treatment). This attitude is demonstrated
more keenly in the treatment for laryngeal cancer
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Surgery vs CTRT in Advanced Laryngeal SCC
FIGURE 3. Organ preservation in the irradiated setting. Comparison among cT2 (in red), cT3 (in green), and cT4a (in blue)
cases.
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FIGURE 4. Survival among cT4a cases. Comparison between
surgery (in blue) and radiotherapy (in red).
surgical, with the codification of partial operations,
and nonsurgical, based on various combinations and
sequences of chemotherapy and radiotherapy, with
the common aim of organ preservation.9–11 In particular, the Veteran Affairs study group demonstrated
that a treatment strategy involving induction chemotherapy and definitive radiation therapy in responders can be effective in preserving the larynx in a high
percentage of patients (64% among survivors in the
irradiated group), without compromising OS (the estimated 2-year survival was 68% for both treatment
groups), compared with total laryngectomy, followed
by adjuvant radiotherapy in the nonresponders
group.12 A more recent study7 demonstrated that primary treatment with radiotherapy and concurrent
cisplatin (100 mg/m2 on days 1, 22, and 43), while
obtaining the same results as for overall survival
(75% at 2 years, 55% at 5 years), was associated with
a significantly higher relapse-free survival (78% vs
61%) and consequently higher larynx-preservation
rate (88% vs 75%) than induction chemotherapy plus
definitive radiotherapy. At present, the concurrent
radiotherapy plus cisplatin as described by Forastiere
et al6 is thus the standard organ-preservation protocol, and a higher percentage of patients with locally
advanced laryngeal cancer are probably retaining
their larynx. In the present study we obtained similar
2-year OS (73%) and DSS (82%) rates, compared with
these larger perspective studies,7,12 even if we also
included in our group the cT4a cases with thorough
cartilage involvement, which were excluded in the
above-cited studies. These inclusion criteria account,
at least in part, for the lower larynx-preservation rate
among irradiated patients in our series (45%), which
is in fact very low, as expected, among cT4a cases
(17%). Furthermore, in the present report, we
observed, as expected, significantly worse OS and
DSS rates among cT4 patients who decided to
undergo primarily nonsurgical treatment.
Among the most frequent malignancies in the
United States, cancers of the larynx and of the uter-
Surgery vs CTRT in Advanced Laryngeal SCC
ine corpus are the only cases without an increase in
the 5-year survival rates during the last 30
years.1,13,14
Many explanations have been suggested to justify
such a trend.15 Among them many authors cite the
increasing push toward surgical and nonsurgical
function preserving treatments16 and some studies,
contradicting the results by the Veteran Affairs Study
Group and Forastiere, reported a survival advantage
for patients treated primarily with surgery,17 leading
us to hypothesize that the reason for the failure in
improving prognosis of laryngeal cancer is the diffusion of chemoradiotherapy as a primary treatment in
stages II, III, and IV.18 Actually, definite scientific statistical proofs supporting such a thesis are lacking,
and the thesis itself does not consider the wide diffusion, not supported by robust clinical evidence, of
organ-preserving operations as well. Our data about
organ-preservation rate and, most of all, the significantly lower survival evidenced in the radiotherapy
group, led us to confirm the recommendation of a primary surgical treatment in cT4a cases, which should
be a total laryngectomy combined with a bilateral
FIGURE 5. Overall survival among patients with (A) and without
(B) clinical node involvement at diagnosis, excluding cT4a
cases. Comparison between radiotherapy (in red) and surgery
(in blue) as primary treatments.
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577
neck dissection, possibly followed by adjuvant RT chemotherapy, unless the patients are included in a
clinical trial for organ/function preservation, as suggested by main international guidelines6 and also
confirmed by recent data.19 Among the other cT classifications our results confirm that radiochemotherapy is a primary treatment modality that warrants a
survival similar to that of total laryngectomy, thus
allowing preserving the larynx in a relevant number
of cases.
As for the failure in improving the prognosis of laryngeal SCCs, other causes have been hypothesized,15
which we try to summarize in the following paragraphs, also in relation to the findings of the present
report.
TNM classification appears in some cases inadequate. For example, it has been observed that
regrouping cases in stages III and IV into locally
advanced disease versus regional metastasis appears
to better predict survival rates.4 In our series there is
a 15% difference (even if without statistical significance: p ¼ .48, Wilcoxon test) in 2-year OS rate,
between stage IV patients with N2–3 and N0–1 nodal
disease.
Despite the multiplicity of clinical prognosticators,
the only consistent clinical predictors for disease control and DSS in laryngeal SCCs are T classifications
and, to a greater extent, N classifications.20–22 The
prognostic stratification of patients with laryngeal
SCC is inadequate since similar patients, affected by
tumors with similar clinicopathologic parameters and
undergoing the same treatment, may differ widely in
prognosis. This is probably explained by the extreme
biological heterogeneity of laryngeal SCCs and contributes to a lack of consistency in treatment planning. Molecular markers may give us a breakthrough
in such heterogeneity.15,23,24
An example of such a lack of consistency is evidenced in the management of cervical lymph nodes,
which is a fundamental component of the overall
treatment strategy, especially for supraglottic tumors,
in which, for example, shared indications for the
treatment of cN0 necks are still lacking.22 In the
present study, when we exclude cT4a cases, we show
a higher survival rate in patients with cNþ, treated
primarily by radiochemotherapy, and in patients with
cN0, primarily treated by surgery; in the absence of
statistically significant differences, however, the
results may be explained by our small numbers, and
such observation needs to be confirmed in larger perspective studies. Second primary tumors (SPTs) notoriously represent the first cause of death in patients
with early-stage disease,21,22,25,26 although their
impact is also probably not negligible on the OS rate
of advanced cases. In our series we recorded 15 other
primaries in 13 patients, in whom the lung is by far
the most frequent site, and in 2 cases this was the
cause of death (50% of the deaths for other causes;
13% of all deaths in our series).
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Surgery vs CTRT in Advanced Laryngeal SCC
Distant metastases have long been considered a
rare and often nondecisive event in laryngeal cancer
because they almost always developed in patients
with regional disease progression. Yet the increased
possibilities to obtain regional control in N2 and even
N3 cases led to an increased number of distant metastases, which become a relevant cause of failure in
such patients.27 In our series we observed 6 cases of
distant metastases (5 in the lungs, 1 in the bones)
and in 2 cases, despite the locoregional control.
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