Advanced squamous cell carcinoma of the lip (T4b) Is HDR-interstitial brachytherapy a successful alternative to the surgical treatment ?

Abstract

Purpose - To describe a clinical case of advanced cancer of the inferior lip, first treated with High Dose Rate (HDR) Brachytherapy (BRTX) as a successful alternative to surgery.
Method- In December 2011 a 54-year-old female came to the Department of
Maxillofacial Surgery for an extended lesion of the inferior lip and cheek mucosa. Was established a treatment planning that did not include the surgical resection and lip reconstruction, as the patient was suffering from severe systemic clinical disorders. The patient was treated with conventional radiotherapy alone which, due to the onset of grade 3 mucositis, was suspended at 40 Gy of dose delivered. Definitive Hight Dose Rate
(HBR) Brachytherapy was applied. HBR-BRTX was performed with a dose of 3 Gy per fraction, two fractions per day at intervals of 6 hours between the two fractions for 6 days.
The patient received a total dose of 18 Gy with HDR-BRTX, which is equivalent to 29.18 Gy of conventional radiotherapy dose. Results - At three years follow-up, the patient is disease-free (neither recurrence of primary tumor nor appearance of laterocervical lympho-nodes are present). Conclusion - HDR-BRTX offers the possibility to treat patients with advanced lip cancer who cannot undergo surgical and/or CHT treatments.

Full text

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Advanced squamous cell carcinoma of the lip
(T4b): Is HDR-interstitial brachytherapy a
successful alternative to the surgical treatment ?
CUTILLI Tommaso1 M.D., Ph.D. - Head of Maxillofacial Surgery
Operative Unit “San Salvatore Hospital” -
University of L’Aquila - Italy
BONFILI Pierluigi2 MD - Physician of Radiotherapy Unit,
“San Salvatore Hospital”, L'Aquila, Italy
OLIVA Antonio3 M.D. – Maxillofacial Surgeon - Maxillofacial Surgery Operative Unit
“San Salvatore Hospital”, L'Aquila, Italy
DI CESARE Ernesto4 M.D., Ph.D. – Head of Radiotherapy Unit
“San Salvatore Hospital” - University of L’Aquila - Italy
1Department of Life, Health & Environmental Sciences, Maxillofacial Surgery Operative
Unit, University of L'Aquila, L'Aquila, Italy.
2Radiotherapy Unit, San Salvatore Hospital, L'Aquila, Italy.
3Maxillofacial Surgery Unit, San Salvatore Hospital, L'Aquila, Italy.
4Department of Biotechnological and Applied Clinical Sciences, Laboratory of
Radiobiology, University of L'Aquila, L'Aquila, Italy.
Equal contribution of Authors.
Corresponding Author
Prof. Tommaso Cutilli
Head of Maxillofacial Surgery Operative Unit “San Salvatore Hospital” and Post-graduate
Maxillofacial Surgery School
University of L’Aquila - Italy
via della Comunità Europea, 13
67100 L’Aquila - Italy
tommaso.cutilli@cc.univaq.it
fax +39.0862.368547

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ABSTRACT
Purpose - To describe a clinical case of advanced cancer of the inferior lip, first treated
with High Dose Rate (HDR) Brachytherapy (BRTX) as a successful alternative to
surgery.
Method- In December 2011 a 54-year-old female came to the Department of
Maxillofacial Surgery for an extended lesion of the inferior lip and cheek mucosa. Was
established a treatment planning that did not include the surgical resection and lip
reconstruction, as the patient was suffering from severe systemic clinical disorders. The
patient was treated with conventional radiotherapy alone which, due to the onset of grade
3 mucositis, was suspended at 40 Gy of dose delivered. Definitive Hight Dose Rate
(HBR) Brachytherapy was applied. HBR-BRTX was performed with a dose of 3 Gy per
fraction, two fractions per day at intervals of 6 hours between the two fractions for 6 days.
The patient received a total dose of 18 Gy with HDR-BRTX, which is equivalent to 29.18
Gy of conventional radiotherapy dose. Results - At three years follow-up, the patient is
disease-free (neither recurrence of primary tumor nor appearance of laterocervical
lympho-nodes are present). Conclusion - HDR-BRTX offers the possibility to treat
patients with advanced lip cancer who cannot undergo surgical and/or CHT treatments.
Key Words: Advanced Lip Cancer - High Dose Rate Brachytherapy
1. INTRODUCTION
Squamous cell carcinoma of the oral cavity ranks as the 12th most common cancer in the
world (Misra et al,2008). Although it can originate from several districts of the oral
cavity, the inferior lip is a frequent site (Meck et al,1991). Treatment of lip cancer
includes single modality surgery, external beam radiotherapy (EBRT) and/or
brachytherapy (BRTX), or various combinations of these modalities with or without
chemotherapy (CHT). The choice of treatment is based on considerations of disease
control, patient's general condition, functional and cosmetic outcomes, and availability of
resources and expertise (Gerbaulet et al,2002).
Usually in the early stages of lip cancer, surgery or brachytherapy (BRTX) are the
elective treatments. They can be mutually used considering the size of the tumor, tumor-
localization in the lip and the expected functional and esthetic results obtained by each
therapeutic option (Ghadjar et al,2012; Mazeron et al,2009). In advanced stage, surgery
represents the treatment of choice because it is often also necessary to perform neck
dissection (Fang,2014; Nabili et al,2008; Ye,2014). In these cases RT is administered
post-operatively. EBRT associated with chemotherapy (CHT) can represent an
alternative therapeutic planning (Hasson,2008).
Herein we report a clinical case of T4b squamous cell carcinoma of the inferior lip in
which BRTX treatment was first used successfully as an alternative to surgery. Based on
this experience we also discuss current indications of BRTX treatment in lip tumors.
1.1 CLINICAL CASE
In December 2011 a 54-year-old female came to the Department of Maxillofacial
Surgery for an extended lesion of the inferior lip. She reported that a single lesion had
appeared in the mucosa of the right inferior lip a few months earlier and had spread in
recent weeks to the whole lip and left cheek mucosa (Figure 1a). The tumor caused
progressive problems in lip movement during eating and speaking due to the hardening
of labial and left retrocommessural soft tissues. During clinical examination, which did
not cause pain, the inferior lip appeared swollen and difficult to move. No pathological
facial or cervical lymph nodes were detected. The patient’s medical history was
characterized by chronic renal insufficiency, chronic bronchitis and Class II (Mild) heart
failure consequent to myocardial infarction occurring in May 2008. Incisional multiple

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biopsies were performed on both lip and cheek mucosa. Anatomopathological
examination confirmed the presence of malignant tissue defined poor differentiated
squamous cell carcinoma. Due to the patient’s renal impairment, staging was obtained by
Magnetic Resonance Imaging (MRI) of the head and neck, instead CT contrast
enhancement. MRI confirmed the absence of expansive nodular lesions in the facial soft
tissues or swollen lymph nodes in the ipsilateral or contralateral laterocervical region.
Finally, considering that the tumor invaded the cheek mucosa, part of masticator space,
the cancer staging was fixed at cT4, cN0, cMx.
Considering the serious comorbidities and the poor general clinical conditions, the
anesthesiologists strongly discouraged the surgical option. Oncologists hypothesized a
concomitant chemo-radiotherapy but considering the high risk of complications, in the
end the possibility of a systemic drug therapy was excluded. Thus, it was decided to treat
the patient with definitive EBRT without any systemic therapy. Following the
international guidelines, the patient was irradiated with 2 Gy fractions; RT was delivered
using 5 fields arrangement (Bellinzona scheme) with 6-mV photons to the tumor and
latero-cervical lymph-nodes for 70 Gy. Three-dimensional CT planning was used to
optimize dosimetry. The radiation fields can be seen in Figure 1b. Starting from the 10 Gy
of RT delivered, the patient reported worsening dysphagia and a slight burning: the oral
cavity presented erithema suggestive of grade 1 mucositis. At 20 Gy of RT it diffuse
mycosis appeared, associated with erythema and ulcers less than 1 cm2 (Grade 2
Mucositis). Miconazole 2% oral gel, prednisone 12.5 mg/die, lidocaine unguentum 7.5%
and lansoprazole 30 mg/die were prescribed to restrain mucositis progression. Plasm Rich
Platelets (PRP) gel application also provided useful results.
The patient,s conditions remained stable up to 30 Gy of RT when a confluent mucositis
appeared, characterized by erythema with ulcers larger than 1 cm2 (Grade 3 Mucositis).
After four weeks of EBRT (40 Gy of dose delivered), a further progression of the
mucositis and an aggravation of the clinical conditions were observed: the patient was
dehydrated and had undergone a 10.8 Kg weight loss. Considering the clinical situation
and that the patient would not be able to continue treatment, the EBRT was suspended.
The patient was hospitalized in order to be rehydrated and subjected to parenteral
nutrition.
Although the international guidelines do not indicate BRXT as a possible therapeutic
strategy in T4b stage lip tumors, with the patient’s consent, continuing radiation therapy
with BRTX, was decided with a definitive curative intent (Figure 1c). With the patient’s
clinical conditions rapidly improving, BRTX was started eleven days after EBRT
suspension. In configuring the implants, the wires were distributed between the inferior
lip and left check, to cover all tumoral lesions present. Thus, 3 active Iridium-192 wires in
tridimensional shape, with a length of 6 cm and a separation of about 0.3 cm between the
wires were programmed to be used. After the simulation, the wires where effectively
implanted, as illustrated in figures 1d and 1e. The treatment consisted in a dose of 3 Gy
per fraction, two fractions per day at interval of 6 hours between the two fractions, for 3
days. The patient therefore received a total dose of 18 Gy with HDR-BRTX, which is
equivalent to 29.18 Gy EBRT dose. The patient was monitored every two months up to
June 2013 and every six months up to June 2014. To date the patient is disease-free.
Neither a recurrence of the primary tumor nor any appearance of laterocervical metastatic
lympho nodes are present (figure 1f).
1.2 DISCUSSION
Oral cancer accounts for 5% -6% of all cancers and its incidence is increasing. Interest
in clinical and basic sciences against squamous cell carcinoma of the oral cavity has also
increased in order to define prognostic markers (Cutilli et al,2013).
The lips, although often overlooked, are not an uncommon site for nonmelanoma skin
cancers (NMSC), including the two most common skin cancers, basal and squamous cell
carcinoma (BCC and SCC).

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Most frequently occurring in fair-skinned males over the age of 50, cancer of the lip
comprises approximately 0.6 percent of all cancers in the US (Young,1981). Studies
showed that males are 3-13 times more likely to develop lip cancers than females, likely
due to occupation-related sun exposure combined with greater tobacco and alcohol use
(Abreu et al,2009). The lower lip is approximately 12 times more likely to be affected,
owing to its greater exposure to sunlight. A recent 25-year retrospective study of 2,152
patients with lip cancer revealed that 81 percent occurred on the lower lip, with males
predominating by 3 to 1 (Molnar et al,1974). Large epidemiological studies have shown
that up to 95 percent of NMSC on the lower lip are SCC (Veness,2001). Given their
highly visible location, the majority of lip cancers are easily detectable and treatable at an
early stage. The most commonly employed treatments include surgery, radiation, and
cryotherapy (freezing with liquid nitrogen), with cure rates for early lesions nearing 100
percent (Mohs et al,1985). Although cancers of the lip have relatively low rates of spread
to nearby lymph nodes and distant sites, the relapse rate after treatment can range from 5-
35 percent, and the mortality associated with large or recurrent SCC of the lip is 15
percent in some studies. Once these cancers spread to local lymph nodes, five-year
survival rates decrease to approximately 50 percent (Zitsch,1995).
Since lip cancer is etiopathogenetically related with exposure to sunlight but often occurs
in subjects which are alcohol and smoke-dependent, and its incidence increases with age,
frequently lip cancer patients present several others health problems that do not permit
wide demolitive surgery and/or CHT approaches. Thus radiation therapy and particularly
EBRT for the late stages, represents the only therapeutic strategy for the treatment. Oral
mucositis is a significant problem in patients undergoing EBRT for oral cancers and
represents a main cause of EBRT interruption and of the consequent therapeutic failure
(Henson et al, 2004; Trotti et al,2003).
1.3 CONCLUSIONS
BRTX is a kind of RT where radioactive sources are placed inside or in contact with the
tumor or inside natural cavities. In the case of lip cancer the radioactive sources are
introduced inside the tumor using specifically designed applicators [4,5]. Indications to
BRTX depend on cancer staging. BRTX is indicated as an exclusive treatment in 90% of
T1 and T2 lip cancers in which Low-Dose-Rate- (LDR-BRTX) or High Dose Rate-BRTX
(HDR-BRTX) can be used [4]. On the other hand, in the T3 and T4a stages, the use of
BRTX is essentially limited to selected cases. Finally, there is no indication for T4b
clinical stage (NCCN, 2013; Aslay et al,2005; Vavassori et al,2012; Liu et al,2013.
The successful experience we report here using BRTX in T4b lip cancer suggests that
BRTX can be used as an extreme ratio in the late stage of lip cancer when others
therapeutic strategies are not feasible .
Moreover no detrimental acute toxicity was observed with brachitherapy but was
registered a gradual symptoms improvement. Xerostomy was the only tardive toxicity.
Thus BRTX should be considered an important resource for such cases.
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Legend of figure.
Fig. 1 – T4b Squamous cell carcinoma of the inferior lip.
a) Black arrows indicate, respectively from the bottom to top, the localization of
multiple ulcerated lesions, the presence of a neoplasm which engages the entire
thickness of the lip causing a bulge, and the lesion on the cheek mucosa. (b)
External beam radiotherapy planning treatment. (c) Brachytherapy planning
treatment. (d) Surgical implantation of wires and (e) three wires implanted. (f)
Clinical aspect of the lip after three years follow-up: absence of relapse.

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Fig. 1