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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2915_Библиотеки_им_академика_М_И_Перельмана.pdf
Hypopharyngeal Cancer
91
Study
Description
VA Larynx
Trial (1991):
332 patients with III/IV larynx (T1N1 excluded), randomized to surgery and post-op RT
(50– 74 Gy) vs. induction cisplatin/5-FU × 2c (with a third cycle if PR/CR) Æ RT (66–
76 Gy). No routine neck dissection for N+ patients. Chemo allowed 64% larynx
preservation at 2 years.
There was no difference in 2-year OS (68%). Chemo-RT decreased distant recurrences,
but had higher LF (12 vs. 2%).
Organ preservation improved quality of life. Salvage laryngectomy was required for
56% of T4 patients.
EORTC
24891
(Lefebvre et
al. 1996):
202 patients with operable pyriform sinus tumors randomized to surgery Æ post-op RT
(50–70 Gy) vs. induction cisplatin/5- FU × 2c (with a third cycle if PR/CR) followed by
RT (70 Gy).
Nonresponders to chemo underwent surgery and RT. Fifty-one to fifty-four percent of
patients had a CR after chemo. There was no difference in LRF, and chemo decreased
DM (36 vs 25%).
The 3/5-year functional intact larynx rates were 42/35% with chemo. On update, no
difference in 5- or 10-year OS and PFS.
RTOG 91–11
(Forastiere et
al. 2003):
547 patients with stage III/IV larynx randomized to one of three arms: RT alone, chemo
Æ RT, or concurrent chemo-RT. RT was 2/70 Gy in all arms. Induction chemo was
cisplatin/5-FU × 2c Æ reassessment.
If progression or <PR, treated with laryngectomy and post-op RT. If PR/CR Æ third
cycle chemo Æ RT. Concurrent chemo was cisplatin × 3c. All patients with cN2 had
neck dissection within 8 weeks after RT.
On update, concurrent chemo-RT improved 5-year larynx preservation (84%) vs.
induction chemo (71%) and RT alone (66%), and LRC (69%) vs. induction chemo
(55%) and RT alone (51%). Chemo reduced the rate of DM (13% concurrent, 14%
induction vs. 22% RT alone) and improved DFS (39% with chemo vs. 27% with RT
alone).
GORTEC
2000–01
(Pointreau et
al. 2009):
220 patients with locally-advanced larynx or hypopharynx cancer that required total
laryngectomy randomized to 3c of TPF (docetaxel, cisplatin, 5-FU) vs. PF (cisplatin, 5FU) chemo.
If CR, PR, and larynx mobility, patients received RT with or without additional chemo;
if no response, patients had surgery and post-op RT with or without additional chemo.
TPF improved overall response (80 vs. 59%) and 3-year larynx preservation rate (70 vs.
58%), but had more neutropenia.
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and
chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med
2004;350:1937-1944.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without
concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med
2004;350:1945-1952.
• Patients with locally advanced (stage III or IV) hypopharyngeal cancer, should be
submitted to a functional organ preservation strategy rather than surgical resection.
• In the clinical practice both concurrent chemoradiotherapy and sequential
chemoradiotherapy are used as a functional organ preservation strategy.
• Chemoradiation is preferred mainly for patients with negative or N1 lymph nodes.
On the other hand, sequential therapy is reserved mainly for patients with high risk of
distant metastases (N3 lymph nodes), as described in table-8.
Table 8. Clinical evidence for chemoradiotherapy in locally
advanced hypopharyngeal cancer
Gustavo Arruda Viani
92
Study
Description
Cetuximab
(Bonner et al.
2006):
424 patients with locoregionally advanced resectable or unresectable stage III–IV SCC
of oropharynx, larynx, or hypopharynx randomized to RT or RT + cetuximab given 1
week before RT and weekly during RT. RT options included 2/70 Gy, 1.2 b.i.d./72–76.8
Gy, or CB 72 Gy.
Cetuximab increased 3-year LRC (34 vs 47%) and OS (45 vs 55%). With the exception
of acneiform rash and infusion reactions with cetuximab, toxicity was similar.
EORTC
24954
(Lefebvre et
al. 2009):
450 patients with resectable T3–T4 larynx or T2–T4 hypopharynx, N0–N2 randomized
to sequential arm (2c cisplatin/5-FU and if >50% tumor reduction, 2 more cycles
cisplatin/5-FU with RT 70 Gy) vs. alternating arm (4 c cisplatin/5-FU in weeks 1, 4, 7,
and 10 alternating with 20 Gy RT during 2-week interval to 60 Gy total).
No difference in larynx preservation, PFS, OS, or acute and late toxicity.
Table 8. (Continued)
References
Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer:
preliminary results of a European Organization for Research and Treatment of Cancer
phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst
1996;88:890-899.
Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for
organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-2098.
Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with
cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl
Cancer Inst 2009;101(7):498-506.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell
carcinoma of the head and neck. N Engl J Med 2006; 354: 567-578.
Lefebvre JL, Rolland F, Tesselaar M et al. Phase 3 randomized trial on larynx preservation
comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst.
2009;101(3):142-52.
• Patients who aren`t candidates for an organ preservation include; patients with
resectable tumors that have destroyed both vocal cords, elderly patients with lower
clinical performance, and those with extensive cartilage destruction from the primary
tumor.
• Management of the neck is complex and, basically, depends upon disease extent,
treatment modality, and response to therapy.
• For patients who are not candidates for a functional organ preserving approach, total
laryngectomy is a potential alternative. Definitive RT alone may be used as a
functional organ preserving approach for hypopharyngeal cancer patients who are not
felt to be candidates for chemotherapy, although there is a higher risk of recurrence
and thus a need for salvage laryngectomy.
• Adequate posttreatment surveillance and long-term follow-up are crucial to ensure
adequate voice and swallowing rehabilitation and to monitor for disease recurrence
or a second primary malignancy.
Hypopharyngeal Cancer
93
Stage
Description
T 1/2 N0
Bilateral II–IV. Include bilateral RP nodes if posterior wall pharyngeal wall involved
T 3/4 N0
Bilateral levels II–IV. Include bilateral RP nodes if posterior pharyngeal wall involved.
Include level VI nodes if tumour extends into cervical oesophagus
qT/N+
Bilateral level II–IV. Level Ib and V nodes on the side of any lymphadenopathy.
Bilateral RP nodes if N2/3 or if posterior pharyngeal wall involved
11. Radiotherapy Techniques
All patients with hypopharyngeal cancer should be planned with CT images due to the
complex volume shape and position. If opposing lateral beams are planed to be used, the
borders can be defined in the simulator on a lateral radiograph.
Patients lie supine on a headrest to keep the spine straight, with a custom-made shell
fixed to the couch top in at least five places to reduce movement. The treated volume will
usually extend inferior to the level of the shoulders which should be as low as possible to
facilitate beam entry.
CT images with 3 mm thick are obtained from the skull base to the carina. The inferior
border is at the carina to facilitate planning with lateral beams angled inferiorly. Intravenous
contrast is to help in the definition of lymph node volumes but is unlikely to add more
information than contrast-enhanced diagnostic imaging which must be available at the time of
target volume definition.
There is as yet no proven role for image fusion with MRI or PET in defining tumor
volumes. The role of PET for target volume definition is evolving and may facilitate dose
escalation by identifying a smaller target volume within the GTV.
The primary tumor site, all nodal beds at risk of containing subclinical disease, and the
entire operative bed should be included in the CTVs. Both ipsilateral and contralateral
posterior nodes should be included in the treatment portals. Areas of initial gross disease,
should receive 70 Gy in 2-Gy-daily, while any area that has a high-risk feature, and any area
that has been dissected should receive 60–66 Gy in 2-Gy-daily increments. Areas that are not
dissected and considered at relatively low risk can receive 44- 54 Gy. The CTVs suggested
for hypopharyngeal tumors is described in table-9.
Table 9. Clinical treatment volume according to tumor and node stage
Intensity-modulated radiotherapy (IMRT) is a new technology from conformal
radiotherapy that by combining several beams of varying intensity achieves improved dose
homogeneity with highly conformal dose distributions. The main advantages of IMRT are
more conformal and homogeneous dose distributions and sparing of normal tissues. Figure 4
shows the homogeneity and highly conformal dose distributions.
For patients whom bilateral nodal irradiation is indicated, conventional radiotherapy
using parallel-opposed fields is often associated with xerostomia. This adverse effect occurs
even when treatment is limited to an elective dose of 46–50 Gy. Xerostomia is resulted of
irradiation of substantial parts of both the parotid and submandibular salivary glands, located
in close proximity to level II neck nodes. IMRT allows unilateral and, in some cases (N0
patients where the superior limit of level II nodes for the electively irradiated neck is set at the
inferior aspect of the transverse process of C1), bilateral parotid gland sparing. The posterior
Gustavo Arruda Viani
94
Organ at risk
Decription
Spinal cord
Maximum dose ≤ 45–50 Gy.
Brainstem
Dose ≤ 54 Gy.
Parotid glands
50% of the volume of each parotid receiving ≤ 20 Gy (if possible) and mean dose <
26 Gy.
Mandible
Mandible maximum dose ≤ 70 Gy.
Brachial
plexus
Brachial plexus dose <60 Gy.
Tracheostomas
Tracheostomas are limited to ≤ 50 Gy unless in tumors with significant subglottic
extension, or emergent tracheostomy, or tumors with extranodal extension in neck
level VI, or with close/+ margin, in which case it is boosted to 60–66 Gy.
Larynx
For other head and neck primary sites, the goal mean dose to the larynx should be
kept below 50 Gy for 2/3 of organ.
But, 70 Gy carries 5% risk of laryngeal cartilage necrosis.
border of the submandibular gland represents the anterior boundary of level II neck nodes,
making them difficult to spare even with IMRT.
Figure 4. CT planning showing isodose distribution with IMRT technique for a T2N1 hypopharyngeal
cancer.
Partial organ radiation of early tumors is possible with IMRT. However, organ motion on
swallowing and the steep dose gradients created with IMRT in a small volume would make
geographical miss a real possibility and, therefore, it is not advised at present. For us, any
reduction in the PTV should be done in the context of clinical studies. Thus, we suggest the
inclusion of the entire larynx, including the thyroid cartilage, in the primary CTV. Other
authors, however, have suggested the inclusion of only the ipsilateral hemi-hypopharynx and
hemi-larynx in piriform fossa and lateral pharyngeal wall tumors.
For locally advanced tumours, at our institution, the entire larynx/hypopharynx complex
is included within the radical CTV, from the tip of the epiglottis to the cricoid cartilage or 2
cm above or below the superior and inferior extent of the tumour, whichever is larger.
The organs at risk are the spinal cord, brain stem, parotid glands, submandibular glands,
mandible, and esophagus. A margin is added to spinal cord and brain stem to obtain a PRV
according to ICRU 62. Dose-limitation guidelines in radiation therapy of hypopharyngeal
malignancies are described in table-10.
Table 10. Limit doses for organ at risks
Hypopharyngeal Cancer
95
For standard fractionation a total dose of 70 Gy at 2 Gy per daily fraction (in 35 fractions
over 7 weeks) to gross disease is indicated. The prescribed dose to subclinical disease is 4450 Gy at 2 Gy per daily fraction. For concomitant boost radiotherapy therapy a total dose of
72.0 Gy is given in 42 fractions over 6 weeks as 32.4 Gy in 18 fractions in 3 weeks (1.8
Gy/fraction/day) to a large field including subclinical disease followed by another 21.6 Gy in
12 fractions (1.8 Gy/fraction) to the same field, and a second daily fraction at least 6 h later
consisting of 18.0 Gy in 12 fractions (1.5 Gy/fraction) to a small “boost field”. For adjuvant
irradiation a Standard fractionation is recommended with a total dose of 60– 66 Gy at 2 Gy
per fraction (in 30–33 fractions over 6–6. weeks), as used in the RTOG randomized trial.
Cisplatin-based chemotherapy (100 mg/m2 IV on days 1, 22, 43) or cisplatin 30 mg/m2 IV
weekly with concurrent radiation therapy is the regimen best supported by the available
literature.
Conclusion
• Hypopharyngeal cancer is an aggressive tumor from head and neck.
• The majority of patients has unfortunately a locally advanced disease at diagnosis.
• There is several options for treating these tumors such as; surgery, radiotherapy,
chemoradiation.
• For an organ preservation approach a multidisciplinary team is necessary, including
radiation oncologist, clinical oncologist and surgeon.
• For organ preservation radiotherapy combined with cisplatin based-chemotherapy is
the standard option. Novel techniques, like intensity modulate radiotherapy ( IMRT)
and image guide radiotherapy (IGRT), can improve the therapeutic index to treat
these tumors.
Chapter 7
Larynx Cancer
Abstract
Tumors of the larynx constitute about 3.5% of all new malignancies diagnosed
annually worldwide.
Tobacco and alcohol are considered the major risk factors for developing larynx
cancer.
The symptoms of laryngeal cancer are hoarseness, sore throat, dysphagia, and
odynophagia.
The diagnostic evaluation and clinical staging of a patient with a suspected
laryngeal cancer involves a history and physical examination followed by
imaging and panendoscopy with biopsy CT and magnetic resonance imaging
(MRI) can detect invasion of the preepiglottic space.
Squamous cell carcinomas comprise 85 to 90% of all laryngeal neoplasms.
The pattern of dissemination of laryngeal cancer basically is related with tumor
stage and origin location.
The clinical stage at diagnosis is the most important prognostic factor for cancer
of the larynx.
Early laryngeal cancer can be treated by definitive radiation therapy (RT) or
larynx-sparing surgery (transoral laser surgery and open partial laryngectomy).
Both treatment modalities generally offer equivalent local tumor control and
survival.
Patients with locally advanced laryngeal cancer, an organ preservation treatment
Tobacco and alcohol are considered the major risk factors for developing larynx cancer.
New efforts in understanding the molecular biology and carcinogenesis of laryngeal cancer
have resulted in a great evolution therapeutic potential. In the last 30 years strategies
combining chemotherapy and radiotherapy have not substantially changed drastically the
survival rate of patients with advanced disease. On the other hand, the main challenge in
laryngeal cancer treatment is improving survival while preserving function by limiting
treatment toxicities. In this chapter we will discuss all aspects involving the radiotherapy
treatment.
rather than surgical resection should be recommended.
Introduction
Gustavo Arruda Viani
98
Tobacco smoking
It is the single most important etiologic factor.
Tobacco contains more than 19 known carcinogens and more than 4,000
chemicals carcinogenic.
Previous radiation
Postcricoid carcinoma is associated with previous radiation exposure;
variously reported in 4 to 7%of cases.
Alcohol
Alcohol use has a synergistic effect with tobacco and is known to increase the
risk of developing head and neck cancer up to 20 to 120 times than of
nonsmoker and nonalcoholic person.
HPV
Although human papilloma virus has been implicated in oropharyngeal
carcinoma, its role in the carcinogensis of hypopharyngeal cancer is less well
defined. Rates of detection range from 19 to 29%.
Plummer–Vinson
Syndrome
The syndrome, which tends to occur in females aged 30 to 50 without a
history of tobacco and alcohol use, is characterized by dysphagia, associated
weight loss and iron-deficiency anemia.
Today the syndrome is rare in regions with improved nutrition and
fortification of food with vitamins and iron.
1. Epidemiology
• Tumors of the larynx constitute about 3.5% of all new malignancies diagnosed
annually worldwide.
• They cause about 200,000 deaths that is about 1% of all deaths from cancer.
• Over the years, squamous cell carcinoma of the larynx has been the most frequent
malignant tumor of the upper aerodigestive tract in Europe, but recent increases in
the incidence of oral and oropharyngeal cancer have narrowed the difference.
• In the United States, where laryngeal cancer accounts for 25 % of the 49,000 cases of
head and neck cancer diagnosed annually, glottic, supraglottic, and subglottic cancers
represent approximately two-thirds, one-third, and two percent of laryngeal cancers,
respectively.
Reference
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin.
2005;55(2):74.
2. Risk Factors
Several risk factors have been identified for head and neck cancer from oropharynx
(Table-1).
Table 1. Risk factors for larynx cancer
Larynx Cancer 99
References
Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels AB, Maisonneuve P, Boyle P. Tobacco
smoking and cancer: a meta-analysis. Int J Cancer. 2008;122(1):155.
Hashibe M, Brennan P, Benhamou S et al. Alcohol drinking in never users of tobacco,
cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis
in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer
Inst. 2007;99(10):777.
3. Anatomy
The larynx is divided into three anatomic regions: the supraglottic larynx, the glottic
larynx, and the subglottic larynx. The supraglottic larynx includes the epiglottis, aryepiglottic
folds, laryngeal surface of the arytenoids, false vocal cords, and ventricles. The glottic larynx
is derived from the tracheobronchial anlage and consists of both true vocal cords and the
mucosa of the anterior and posterior commissures. It extends from the lateral-most apex of
the laryngeal ventricle to 1 cm below the free edge of the vocal folds toward the cricoid. It
has few, if any lymphatics. The subglottic larynx consists of the region bounded by the glottis
above and the inferior border of the cricoid cartilage. Lymphatic supply to the subglottic
larynx is extensive and bilateral. The infraglottic lymphatics drain to the cervical nodes
through the cricothyroid membrane, while supraglottic lymphatics drain through the
thyrohyoid membrane (figure-1).
Figure 1. Larynx anatomy.
Gustavo Arruda Viani
100
4. Clinical Features
• The symptoms of laryngeal cancer are hoarseness, sore throat, dysphagia, and
odynophagia.
• Hoarseness is an early symptom of glottic cancer but may be seen later in advanced
supraglottic or subglottic tumors signifying spread to the vocal cord, arytenoid or
cricoarytenoid joint.
• Paraglottic spread can occur submucosally from these sites to produce hoarseness
without any mucosal irregularity.
• Sore throat and dysphagia are more commonly associated with supraglottic tumors,
and odynophagia signifies involvement of the hypopharynx or tongue base.
• Referred otalgia generally indicates base of tongue involvement but may also be
seen in tumors that have extended into the neck through cartilage.
• Ulceration and bleeding from exophytic tumors may present as hemoptysis. Dyspnea
and stridor occur with bulky supraglottic tumors or in the presence of vocal cord
fixation.
• A neck mass almost always indicates lymphatic metastasis but may result from direct
extension of the tumor into the soft tissues of the neck.
Reference
Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1-T2N0 squamous cell carcinoma
of the glottic larynx treated with radiation therapy. J Clin Oncol. 2001;19(20):4029.
5. Diagnosis and Evaluation
• The diagnostic evaluation and clinical staging of a patient with a suspected laryngeal
cancer involves a history and physical examination followed by imaging and
panendoscopy with biopsy CT and magnetic resonance imaging (MRI) can detect
invasion of the preepiglottic space.
• Signs of preepiglottic space invasion include loss of normal fat density and absent
visualization of the superior extent of the lateral cricoarytenoid muscle.
• Radiographic assessment is also useful to assess subglottic extension and the status
of the laryngeal ventricle in glottic primaries.
• Although CT and MRI are excellent for assessing subglottic extension, coronal MR
reconstruction may be better at delineating ventricular and paraglottic submucosal
spread.
• MRI may also be superior at differentiating thyroarytenoid muscle invasion from
involvement of the cricoarytenoid joint as the cause of vocal cord fixation.
• The value of CT in detecting cartilage invasion is doubtful because of the
inconsistent mineralization patterns (figure-2).
• If the sclerotic appearance of the cartilage is taken as a radiologic marker, only 46%
of patients actually show histologic features of cartilage invasion. Another study