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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2915_Библиотеки_им_академика_М_И_Перельмана.pdf
Oropharyngeal Cancer
71
Studies
Description
Charbonneau
et al (2006)
164 patients treated consecutively for squamous cell carcinoma of the tonsillar region
All patients received curative radiotherapy. No patient received surgery as a primary
treatment modality.
The median follow-up was 4.2 years for all patients and 5.4 years for alive patients.
The overall LRC rate was 72% at 5 years. By T and N stage, local and regional control
rates at 5 years were as follows: T1, 82%; T2,74%; T3, 66%; T4, 65%; N0, 77%; N1,
83%; N2, 65%; and N3, 38%. The overall survival (OS) rate was 57% at 5 years. By T
and N stage, OS at 5 years was as follows: T1, 62%; T2, 67%; T3, 45%; T4, 22%; N0,
63%; N1, 70%; N2, 46%; and N3, 32%.
Mendenhall
et al. (2006)
503 patients underwent to radiotherapy with a planned neck dissection (57 patients) or
received induction (18 patients) or concomitant (39 patients) chemotherapy was
retrospectively analyzed.
The 5-year local control rates were as follows: T1, 88%; T2, 84%; T3, 78%; and T4,
61%. Multivariate analysis revealed that local control was significantly influenced by
T stage, primary site, and fractionation.
Local control after RT for early stage cancers was higher for tonsillar fossa/posterior
pillar tumors than for those arising from the anterior tonsillar pillar.
The 5-year cause-specific survival rates were as follows: I, 100%; II, 86%; III, 84%;
IVA, 73%; and IVB, 46%.
References
Chera BS, Amdur RJ, Hinerman RW, Morris CG, Villaret DB, Werning JW, Mendenhall
WM. Definitive radiation therapy for squamous cell carcinoma of the soft palate. Head
Neck. 2008;30(8):1114.
Erkal HS, Serin M, Amdur RJ, Villaret DB, Stringer SP, Mendenhall WM. Squamous cell
carcinomas of the soft palate treated with radiation therapy alone or followed by planned
neck dissection. Int J Radiat Oncol Biol Phys. 2001;50(2):359.
Tonsillar Cancer
• Both primary surgery and RT can be used to treat early tonsillar tumors due to their
similar outcomes.
• Due to its potentially better functional outcome and good rates of local control,
primary RT has been preferred rather than surgery.
• However, small tumors limited to the tonsil can be treated with a simple
tonsillectomy. For tumors that extend beyond the tonsil, the surgery must include
pharyngeal wall and/or soft palate to achieve negative margins (table- 5).
Table 5. Clinical evidence for curative treatment in tonsillar cancer
References
Charbonneau N, Gélinas M, del Vecchio P, Guertin L, Larochelle D, Tabet JC, Soulières D,
Charpentier D, Nguyen-Tân PF. Primary radiotherapy for tonsillar carcinoma: a good
alternative to a surgical approach. J Otolaryngol. 2006;35(4):227.
Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Malyapa RS, Werning JW,
Lansford CD, Villaret DB. Definitive radiotherapy for tonsillar squamous cell carcinoma.
Am J Clin Oncol. 2006;29(3):290.
Gustavo Arruda Viani
72
Studies
Description
Zhen et al
(2004)
16,188 cases were extracted from the National Cancer Data Base (NCDB).
Five-year observed and disease-specific survival rates were 27.8% and 40.3%,
respectively.
Poorer survival was significantly associated with older age, low income, and
advanced-stage disease.
For early-stage disease, surgery with or without irradiation had higher survival than
irradiation alone. For advanced-stage disease, surgery with irradiation had the highest
survival.
Survival rates were low for base of tongue SCC, with most deaths occurring within
the first 2 years. Income, stage, and age were significant prognostic factors.
Sessions
et al. (2003)
This was a retrospective study of 262 patients with base of tongue cancer treated by
surgery and /or radiotherapy.
The overall 5-year disease-specific survival (DSS) was 49.6% with death due to
tumor in 50.4%.
Local-regional recurrence occurred in 26% of patients, and overall salvage was
10.5%. Patients with clear resection margins did better than patients with close or
involved margins (DSS and CDSS).
Patients treated with radiation therapy alone had improved capacity to swallow (P
=.001), speak (P =.01), and work (P =.001) compared with patients treated with the
other modalities.
Base of Tongue
• Tumors from base of tongue have a more aggressive behavior than other tumors from
the same site. Consequently, as RT as surgery are associated with lower diseasespecific survival compared with other oropharyngeal cancers.
• This aggressive behavior can be explained because of the higher risk of occult lymph
node metastasis than the other oropharyngeal subsites, ranging from 20 to 45 %.
• Surgery for early unilateral base of tongue cancer consists of hemiglossectomy. But,
more radical resection and selective neck dissection as single modality for stages I
and II, followed for surgical reconstruction is used to optimize functional outcomes
(table – 6).
Table 6. Clinical evidence for curative treatment in base of tongue
References
Zhen W, Karnell LH, Hoffman HT, Funk GF, Buatti JM, Menck HR. The National Cancer
Data Base report on squamous cell carcinoma of the base of tongue. Head Neck.
2004;26(8):660.
Sessions DG, Lenox J, Spector GJ, Chao C, Chaudry OA. Analysis of treatment results for
base of tongue cancer. Laryngoscope. 2003;113(7):1252.
Adjuvant Treatment
• Generally, early stage disease (Stage I and II) are managed initially with either RT or
surgery. Thus, patients should receive postoperative RT with or without concurrent
chemotherapy for positive or close resection margins, extracapsular extension of
lymph node disease, or other high risk features, such as lymphovascular and
perineural invasion (table – 7).
Oropharyngeal Cancer
73
Study
Decription
EORTC 22931 (Bernier
et al. 2004)
334 patients with operable stage III/IV oral cavity, oropharynx, larynx, and
hypopharnx cancer randomized to post-op RT (2/66 Gy) vs. post-op chemoRT (2/66 Gy and cisplatin 100 mg/m2 on days 1, 22, 43).
All patients received 54 Gy to the low-risk neck. Eligible stages included
pT3–4N0/+, T1–2N2–3, and T1–2N0–1with extra capsular extension,
+margin,or perineural invasion.
Chemo-RT improved 5-year DFS (59 vs 47%), 5-year OS (65 and 53%), and
5-year LRC (82%), but increased grade 3–4 toxicity (21 and 41%).
RTOG 95–01 (Cooper
et al. 2004)
459 patients with operable cancer of the oral cavity, oropharynx, larynx, or
hypopharynx who had 2 or more involved lymph nodes, nodal extracapsular
extension, or a + margin were randomized to post-op RT (2/60–66 Gy) vs.
post-op chemo-RT (2/60–66 Gy and cisplatin ×3 c).
Chemo-RT improved 2-year DFS (43 vs 54%), LRC (72 vs 82%), and had a
trend for improved OS (57 and 63%), with increased grade 3–4 toxicity (34
and 77%).
Pooled RTOG/EORTC
analysis (Bernier 2005)
Chemo-RT improved OS, DFS, and LRC for ECE and/or + margins, but
provided only trend for improvements (p > 0.06) for stage III–IV, PNI,
LVSI, and/or enlarged LN in levels IV–V.
Table 7. Clinical evidence for adjuvant radiotherapy combined
or not with chemotherapy
References
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck
cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy
trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27(10):843-50.
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.
10.2. Advanced Stage Disease
• Treatment of locally advanced oropharynx cancer (stages III and IVA/B) requires a
multidisciplinary team approach in order to provide optimal therapy.
• Selection of which patients with locally advanced disease are best treated with organ
sparing approaches versus primary surgery is complex.
• For most patients with locally advanced oropharyngeal cancer, an organ preservation
strategy rather than surgical resection have been suggested.
• Concurrent chemoradiation and sequential therapy (induction chemotherapy
followed by concurrent chemoradiotherapy) are effective organ function preservation
approaches.
• Some experts suggest concurrent chemoradiotherapy for patients with N0-2
presentations and sequential therapy for patients with high risk of distant metastases,
ie, advanced nodal presentations (N3).
Gustavo Arruda Viani
74
Study
Decription
Posner et al.
(2007):
Randomized 501 patients with unresectable stage III–IV head and neck cancer to TPF
(docetaxol/ cisplatin/5-FU) vs. PF (cisplatin/5-FU) induction chemotherapy followed
by carboplatin chemo-RT (70–74 Gy).
Induction TPF improved LRC and 3-year OS (48 vs 62%), but not DM. Up to 25% of
patients did not receive concurrent chemo-RT due to progressive disease, adverse
events, death, or withdrawal of consent.
(Vermorken et
al. 2007):
Randomized 358 patients with unresectable stage III–IV head and neck cancer to TPF
(docetaxol/cisplatin/5-FU) vs. PF (cisplatin/5-FU) induction chemotherapy followed
by RT alone, delivered with conventional (66 Gy) or hyperfractionated (74 Gy) RT.
Induction TPF increased MS (14.5→18.8 months), but increased hematological
toxicity and chemo-related death (2.3 vs. 5.5%). Up to 15% percent of patients were
unable to receive RT.
Pignon et al.
(2009)
93 phase III trials and 16,485 patients. 4.5% OS benefit at 5 years when
chemotherapy was added to RT, with greater benefit for concurrent chemo-RT vs.
induction chemo followed by RT (6.5% OS benefit with concurrent chemo-RT).
Similar results in trials with post-op RT, conventional, and altered fractionation.
No difference between mono or polychemotherapy regimens, but increased benefit
with platinum-based compounds.
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.
• Patients who are not candidates for treatment with platinum-based therapy,
cetuximab with RT is another option.
• For patients with a good performance status being treated with concurrent
chemoradiotherapy, cisplatin (100 mg/m2 every three weeks) concurrent with RT has
the best established efficacy.
• Low dose cisplatin (30 to 40 mg/m2 weekly) concurrent with RT is also an option,
particularly for patients with a diminished performance status.
• An alternative to sequential therapy or concurrent chemoradiotherapy is induction
chemotherapy followed by radiation therapy (RT), though this approach has been
associated with reduced locoregional control (table – 8).
• On the other hand, definitive RT remains a treatment option for elderly patients and
those with a poor performance status.
Table 8. Clinical evidence for chemoradiation in locally advanced head and neck cancer
References
Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with
docetaxel in head and neck cancer. N Engl J Med 2007;357(17):1705-1715.
Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in
unresectable head and neck cancer. N Engl J Med 2007;357(17):1695-1704.
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.
Oropharyngeal Cancer
75
Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and
neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
Radiother Oncol. Jul 2009;92(1):4-14.
11. Radiotherapy Technique
The patient lies supine with the spine as straight as possible and no mouth bite, but any
dentures should be left in place. A shell is constructed to ensure immobilization (figure 3).
Figure 3. Thermoplastic mask system extending from vertex of scalp to shoulders for immobilization of
the patient in the treatment of oropharynx.
CT images with intravenous contrast are acquired with 3 mm thick slices from the skull
base superiorly to the top of the aortic arch inferiorly. Lateral and midline reference marks are
drawn on the mask. The CT dataset is imported into the treatment planning system. Many
oropharyngeal tumours are more easily defined with MRI than CT so co-registered images
may improve GTV definition. The GTV is drawn on the films with the help of diagnostic
clinical information and imaging. The CTVs and PTVs are then defined as for CT planning
and beam arrangements chosen.
The GTV is defined as the primary tumour and any lymph nodes over 10 mm in short
axis dimension or smaller nodes with necrotic centres or rounded contours thought to contain
tumour. A high dose CTV70 is created to include sites of local and nodal spread and a lower
dose CTV44 to include uninvolved nodal levels to receive a prophylactic dose. The GTVCTV70 expansion at the primary site is individualized and nonuniform reflecting local
barriers to spread and the possible involvement of local structures. For N0 tumours, the
CTV70 will include level II nodes adjacent to the primary either ipsilaterally (lateral tonsil or
soft palate primary) or bilaterally. In node positive disease the CTV70 includes all levels with
involved lymph nodes and those adjacent to the primary site (figure 4).
Gustavo Arruda Viani
76
Lateral tonsil or soft palate T1/T2
N0/N1
Ipsilateral levels II–IV (and Ib, RP, retrostyloid if N1)
Lateral tonsil or soft palate T1/T2
N2a,b
Ipsilateral levels Ib–IV, retrostyloid, RP and consider
ipsilateral level V
Base of tongue, midline soft palate
T1/T2 N0/N1
Bilateral levels II–IV (and RP if posterior pharyngeal
posterior pharyngeal wall T1/T2 N0 wall involved)
Tonsil or soft palate T 3/4 and/or N2 or
N3
Consider each hemi-neck separately: N+ neck – levels
N2c, N3 Ib–IV, retrostyloid and RP nodes and consider level V
Base of tongue, midline soft palate
Any T 3/4 and/or N + wall involved)
N0 neck – levels II–IV (and RP if posterior pharyngeal)
Figure 4. GTV contour definition illustrating the primary tumor and an adjacent involved node. The
close proximity of these two lesions requires one GTV volume for planning (GTV).
If there is involvement of an adjacent muscle due to extracapsular spread, this should be
included in the CTV70. There is no evidence correlating CT data with pathological specimens
from which to derive a GTV-CTV margin. In practice, the CTV70 is best achieved by
automatically growing the GTV by 10 mm (the pathological margin that a surgeon aims for),
and editing it, to include sites of local spread and possible nodal involvement and to exclude
soft tissues where there are natural barriers to tumour spread, air spaces and uninvolved bone.
A low dose CTV44 is created from the CTV70 by also including other lymph node sites
thought to be at risk of microscopic nodal disease. If this volume is to be treated with a single
anterior neck beam, a 3D volume need not be defined. If the posterior pharyngeal wall is
involved the bilateral retropharyngeal nodes should be included in the CTV44. The nodal
levels to be included in the CTV44 for different tumours are given in Table 9.
Table 9. Recommendations for designing CTV 44 – 50 Gy in oropharyngeal cancer
Oropharyngeal Cancer
77
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.
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. Dose-limitation guidelines in radiation therapy of oropharyngeal malignancies are
described in table-10.
Table 10. Limit doses for organ at risks
Figure 4. Isodose lines and DVH distribution for IMRT in oropharyngeal cancer.
Gustavo Arruda Viani
78
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 5 6 shows the homogeneity and highly conformal dose distributions.
Figure 5. Isodose lines from 3D and IMRT treatment for oropharyngeal cancer, showing a reduction of
irradiated normal tissue.
References
Chao KS, Ozyigit G, Blanco AI et al (2004) IMRT for oropharyngeal carcinoma: impact of
tumor volume. Int J Radiat Oncol Biol Phys 59:43–50
Eisbruch A, Harris J, Garden AS et al (2010) Multi-institutional trial of accelerated
hypofractionated IMRT for early-stage oropharyngeal cancer. Int J Radiat Oncol Biol
Phys 7:1333–1338
Yao M, Dornfeld KJ, Buatti JM et al (2005) IMRT for head-and-neck SCC – the University
of Iowa experience. Int J Radiat Oncol Biol Phys 63:410–421
de Arruda FF, Puri DR, Zhung J et al (2006) IMRT for the treatment of oropharyngeal
carcinoma: the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol
Biol Phys 64:363–373
Oropharyngeal Cancer
79
Lawson JD, Otto K, Chen A et al (2008) Concurrent platinum-based chemotherapy and
simultaneous modulated accelerated RT for locally advanced SCC of the tongue base.
Head Neck 30:327–335
Conclusion
• In the last decades the treatment of patients with cancer of the oropharynx are
evolving.
• The increasing availability of highly conformal irradiation techniques, like IMRT, is
promoting a reduction in the incidence and severity of normal tissue toxicities.
• The advances in molecular targeting agents can produce new treatment options for
patients with both locoregional and metastatic/recurrent disease.
• On the other hand, advances in surgical technology can open new opportunities to
tailor therapy and reduce toxicities.
