© Borgis - Postępy Nauk Medycznych 2/2011, s. 116-122
*Andrzej Kawecki, Romuald Krajewski
Rak płaskonabłonkowy narządów głowy i szyi: aktualne zasady postępowania i perspektywy
Squamous cell carcinoma of head and neck organs: contemporary management and perspectives
Head and Neck Cancer Department, Centre of Oncology – M. Sklodowska-Curie Memorial Institute, Warsaw, Poland
Head of Department: prof. dr hab. med. Andrzej Kawecki, MD
Streszczenie
Rokrocznie w Polsce stwierdza się ok. 5600 nowych zachorowań na nowotwory narządów głowy i szyi. Ponad 90% spośród nich stanowią przypadki raka płaskonabłonkowego, w tym najczęściej raka krtani (ok. 40%). Czynniki kancerogenne są dobrze zdefiniowane i stanowią w tej grupie przyczynę wysokiego ryzyka (0,015-0,05/rok) zachorowania na drugi, niezależny nowotwór. Patomorfologicznie, wyróżnia trzy stopnie złośliwości raka (G1-G3), przy czym G1 oznacza nowotwór o wysokim stopniu zróżnicowania, a G3 niski stopień zróżnicowania. Podział patomorfologiczny ma istotne znaczenie prognostyczne, podobnie jak przerzuty w zakresie regionalnych węzłów chłonnych (N0-N3). Leczenie większości chorych, u których rozpoznawane są nowotwory o znacznym stopniu zaawansowania miejscowego i regionalnego, powinno być prowadzone przez zespół wielodyscyplinarny. Dobór postępowania zależny jest głównie od stopnia zaawansowania raka i jego lokalizacji w zakresie narządów głowy i szyi. Wyjściowo znaczne zaawansowanie stwierdzane jest u większości chorych. Leczenie może mieć charakter radykalny, paliatywny lub też wyłącznie objawowy. Postępy leczenia w ciągu ostatnich lat obejmują przede wszystkim wdrożenie nowoczesnych technik rekonstrukcyjnych w zakresie ubytków pooperacyjnych z uwzględnieniem płatów zespalanych mikrochirurgicznie, zwiększenie precyzji radioterapii przykładowo poprzez szerokie wdrożenie napromieniania o modulowanej intensywności wiązki, kliniczną aplikację jednoczesnej chemioradioterapii oraz wprowadzanie do praktyki leczenia ukierunkowanego molekularnie. Przykładowo, dodanie inhibitora szlaku sygnałowego naskórkowego czynnika wzrostu (EGFR) do radioterapii skutkuje poprawą odsetka wieloletnich przeżyć całkowitych o ok. 9%. Nowe strategie leczenia stanowią stopniowy postęp, tym niemniej w dalszym ciągu najbardziej prostą i bezpieczną strategią pozwalającą na poprawę rokowania jest rozpoznawanie raka we wczesnym stopniu zaawansowania.
Summary
Some 5600 head and neck malignancies are diagnosed each year in Poland. Among them squamous cell carcinoma constitutes over 90%, and 40% are carcinomas of larynx. Risk factors are well-defined and contribute to relatively high incidence (0.015-0.05/year) of second independent malignancies in these patients.
Pathological assessment should include malignancy grading (G1-G3) where G1 is well-differentiated and G3 non-differentiated tumor. It is one of strong prognostic factors along with regional lymph node status (N0-N3).
Management of a vast majority of patients who present with an advanced head and neck squamous cell carcinoma should be carried out by a multidisciplinary team. Principles of management are relatively complex due to multiplicity of organs and localizations in head and neck region. More than half of patients present with an advanced disease. Decision has to be made whether management with curative intent, palliative antineoplastic treatment or symptomatic/supportive management is indicated.
Recent advances in management of head and neck squamous cell carcinoma include improved reconstruction of post-resection defects with free microsurgical tissue transfer, improved precision of irradiation with intensity modulated radiation therapy, application of radiochemotherapy with cisplating and other chemotherapuetics, implementation of therapy acting through molecular targets. EGFR inhibitor cetuximab added to radiotherapy improved overall survival by 9%.
These improvements brought an incremental improvement but early diagnosis still remains the best and the safest way to improve outcomes in patients with squamous cell carcinomas of head and neck.
Introduction
More than 90% of head and neck (H&N) organs malignancies are squamous cell carcinomas (SCC). In Poland H&N tumors constitute 5.6% of all malignant tumors and 5600 new cases are diagnosed each year (1). Squamous cell head and neck cancer (SCHNC) is much more frequent among men, with male/female ratio of 4.5-5/1. Larynx is the most common site, and in men SCC of larynx constitutes 4% of all newly diagnosed malignancies. The highest incidence of SCHNC is in people aged over 50. During last decade the incidence in Poland was rather stable, with slight increase seen among women.
Surgery and radiotherapy (RTH) are traditional, well-established methods of treatment for SCHNC. In early stages of disease (T1-2, N0) these methods used alone or in combinaton give satisfactory outcomes. In advanced stages, which are seen in about 70% of newly diagnosed cases in Poland and in other countries, combined surgery and RTH or radiochemotherapy (RCTH) are used, but results continue to be unsatisfactory with 5-year survival of only 30-40%. Additional problems arise from significantly increased rate of treatment toxicity in patients undergoing RCTH. New treatment protocols, in particular targeted therapies, are intensively investigated in order to improve outcomes in this poor-prognosis, advanced disease group, as well as in recurrent or metastatic SCHNC.
Etiology and pathology of SCHNC
SCHNC arises in mucosa of head and neck organs. Localization in the larynx is the most frequent (40% of all SCHNC), then in decreasing order of incidence in oropharynx, oral cavity, lower lip, hypopharynx, paranasal sinuses and nasal cavity (2).
Carcinogens in SCHNC are well-defined and include tobacco smoke (SCC of larynx and oropharynx), alcohol (oral cavity, oropharynx, hypopharynx), chronic mechanical irrtation (oral cavity). These factors also cause high risk of second, independent malignancy, mainly in respiratory system. Such tumors arise in 0.015-0.05 patients per year (3). Recently, human papilloma virus (HPV) infection has been identified as an etiologic factor in selected SCHNC, particularly those of oropharynx and oral cavity. SCCs related to HPV infection are more sensitive to radiation and carry a better prognosis.
SCHNC cells show multiple molecular abnormalities. Suppressor gene mutations, amplification of oncogenes, chromosomal aberrations, overexpression of growth factors lead to progression of tumors and cause resistance to treatment. Expression of epidermal growth factor receptor (EGFR), and activation of its signaling pathway are found in almost all SCHNCs. Radiation is one of factors stimulating this expression, and it is at the same time the treatment modality used in vast majority of patients. Activation of EGFR-dependent tyrosine kinase pathway results in proliferation, migration and invasion of tumor cells, as well as in reduced apoptosis and in angiogenesis. Clinical equivalents of these processes are progression of the tumor and resistance to radiotherapy and chemotherapy (CTH), caused mainly by reduced apoptosis, which facilitates repair of damages caused by treatment (4).
Pathological assessment of SCHNC classifies these tumors into 3 grades of differentiation. G1 is a highly differentiated SCC, G2 is intermediate and G3 is non-differentiated (2). Majority of oral cavity, larynx, hypopharynx tumors are G1 or G2, while G3 tumors are frequent in oropharyngeal localization. This grading has significant clinical impact, as G1 and G2 tumors tend to grow slowly and give distant metastases in 15-20% (2). G3 tumors grow more rapidly, distant metastases appear earlier, with high frequency. However, high-grade, non-differentiated SCC is more sensitive to RTH and CTH.
Management plan
Management plan is a critical element in diagnosis and treatment of SCHNC. First line of treatment determines an outcome, because of very limited efficacy of second line treatment. Decision on the most appropriate treatment plan has to take into account both tumor-related and patient-related factors. Clinical staging according to TNM/AJCC classification, tumor localization and pathological grade are the most important. There is growing evidence that molecular characteristic of the tumor and HPV infection will soon be also used. Important factors that relate to patient are functional and nutritional status, and co-morbidities (3).
The above factors determine whether treatment with curative intent will be possible. Such treatment is preferred for patients with local and loco-regional disease. The optimal decision process leading to formulation of management plan should be a discussion in an interdisciplinary oncology panel/team. Only in early stages, when therapeutic options are very well defined, single specialist management (surgery or RTH) is appropriate.
Treatment strategy that gives higher probability of cure should be preferred. If two strategies have similar probability of achieving cure, functional outcome and patient preference should decide. Individual patient factors that will determine treatment tolerance have to always be taken into account. Eventually, treatment plan, available options, risks and expected outcomes should be presented to the patient, who will make decision and give his informed consent.
Treatment with curative intent
Clinical stage of disease according to TNM/AJCC staging system determines treatment modality. In cT1-2N0 stages surgical therapy, RTH or combination of these methods are indicated and result in 60-90% 5-year survival (2, 3). Prognosis significantly depends on localization. The highest cure rate is typical for glottic cancer, whilst cancer of hypopharynx carries the worst prognosis. Functional and cosmetic results in these cases are satisfactory, along with good quality of life.
RTH should be planned and delivered on the basis of three-dimensional reconstructions of diagnostic images. Conventional fractionation regime is commonly used, but efficacy of accelerated RTH has also been demonstrated (3, 5). RTH as single method has strictly defined indications which include SCC of larynx, hypopharynx and oropharynx (3). In T1N0 and in selected T2N0 interstitial brachytherapy is an accepted alternative.
Surgical resection is indicated in early stage SCC of oral cavity, lower lip and paranasal sinuses. If resection with organ preservation is possible, T1-2N0 cancer of the larynx can also be treated surgically (3). Oncological results are similar to those of RTH, but quality of voice appears to be better after irradiation.
Combination of surgery and RTH in SCHNC is used exclusively as an initial resection followed by adjuvant irradiation (2, 3). Indications for combined treatment have to be based on detailed pathological examination of surgical specimen. In case of close surgical margins (less than 5 mm), dispersed infiltration by tumor cells, low grade tumor (G3), invasion of deep muscles, cartilage or bone (pT4) irradiation is indicated (3). When pathology shows non-radical resection R2 (macro- or microscopic), a reoperation should be the first option. If it is not possible, radical radiotherapy should be delivered.
It is accepted that metastasis to even a single regional lymph node makes an indication for adjuvant RTH. When more unfavorable prognostic factors, as extracapsular spread or metastases to multiple lymph nodes (> 2) are present, more aggressive adjuvant therapy is advised, including RCTH based on cisplatin (3, 6, 7). Principles of adjuvant therapy presented above are applicable also to more advanced SCHNC.
Patients with SCHNC in clinical grades III and IV (cT3-4 cN1-3) present very difficult challenges. In Poland, but also in other developed countries, some 2/3 of newly diagnosed cases are in these grades. Traditional surgery and RTH combination gives 5-year loco-regional control in less than 40%. Results are slightly better in SCC of larynx and lower lip. Moreover, risk of distant metastases is significantly higher in this group, particularly if large metastases to neck lymph nodes are present. Intensive clinical research conducted in 90s resulted in new standard of conservative treatment for advanced SCHNCs. Concurrent radiotherapy and chemotherapy improved long-term survival by 7-25% in comparison to RTH alone (8-12). RCTH proved to be the best organ-preservation treatment, an useful alternative to disfiguring surgical procedures and more efficient alternative to RTH as adjuvant therapy in cases with poor prognostic factors (6, 7, 13).
Results from randomized trials have been confirmed by metaanalyses, which showed 8-11% improvement in survival after RCTH. It has been demonstrated that combination of irradiation with cisplatin is the most efficient, and that therapeutic gain does not depend on RTH fractionation regime (14-17).
The above-mentioned findings have established contemporary standard of care for grade III-IV SCHNC, which is either surgery with adjuvant RTH/RCTH, or RCTH in patients who cannot be operated upon or are candidates for organ-preservation treatment.
Surgery is preferred as an initial treatment for patients with SCC of oral cavity, larynx, paranasal sinuses and in cases of SCC of oropharynx or hypopharynx where non-surgical therapy is contraindicated (3). Surgical procedures have to include same-stage closure of resection cavity with local flaps, distant pediculate flaps or free flaps with microvascular anastomosis. Availability of a wide range of reconstruction methods is necessary to achieve acceptable functional and cosmetic result, particularly after an extensive resection.
Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Mam kod dostępu
- Aby uzyskać płatny dostęp do pełnej treści powyższego artykułu albo wszystkich artykułów (w zależności od wybranej opcji), należy wprowadzić kod.
- Wprowadzając kod, akceptują Państwo treść Regulaminu oraz potwierdzają zapoznanie się z nim.
- Aby kupić kod proszę skorzystać z jednej z poniższych opcji.
Opcja #1
29 zł
Wybieram
- dostęp do tego artykułu
- dostęp na 7 dni
uzyskany kod musi być wprowadzony na stronie artykułu, do którego został wykupiony
Opcja #2
69 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 30 dni
- najpopularniejsza opcja
Opcja #3
129 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 90 dni
- oszczędzasz 78 zł
Piśmiennictwo
1. Wojciechowska U, Didkowska J, Tarkowski W, Zatoński W: Nowotwory złośliwe w Polsce w 2003 roku. Centrum Onkologii – Instytut im. Marii Skłodowskiej-Curie, Warszawa 2005.
2. Vokes EE, Wichselbaum RR, Lippman S, Hong WK: Head and neck cancer. N Eng J Med 1993; 328: 1318-1324.
3. Jassem J, Kawecki A, Krajewski R et al.: Nowotwory nabłonkowe narządów głowy i szyi. Zalecenia diagnostyczno – terapeutyczne w nowotworach złośliwych u dorosłych. Red. Krzakowski M. Via Medica, Gdańsk 2007; 1-33.
4. Ang KK, Berkey BA, Tu X et al.: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62: 7350-7356.
5. Hliniak A, Gwiazdowska B, Szutkowski Z et al.: A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall treatment time. Radiother Oncol 2002; 62: 1-10.
6. Bernier J, Domenge C, Ozsahin M et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Eng J Med 2004; 350: 1945-1952.
7. 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 Eng J Med 2004; 350: 1937-1944.
8. Huguenin P, Beer KT, Allal A et al.: Concomitant cisplatin significantly improved locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol 2004; 22: 4665-4673.
9. Brizel DM, Albers ME, Fisher SR et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Eng J Med 1998; 338: 1798-1804.
10. Denis F, Garaud P, Bardet E et al.: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004; 22: 69-76.
11. Jeremic B, Shibamoto Y, Milicic B et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective, randomized trial. J Clin Oncol 2000; 18:1458-1464.
12. Wendt TG, Grabenbauer GG, Rodel CM et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998; 16: 1318-1324.
13. Forastiere AA, Goepfert H, Maor M et al.: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Eng J Med 2003; 349: 2091-2098.
14. Browman GP, Hodson DI, Mackenzie RJ et al.: Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of published literature with subgroups analysis. Head Neck 2001; 23: 579-589.
15. Munro AJ: An overview of randomized controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995; 12: 385-395.
16. Pignon JP, Baujat B, Bourhis J: Individual patient data meta-analysis in head and neck carcinoma: what have we learnt? Cancer Radiother 2005; 9: 31-36.
17. Pignon JP, le Maitre A, Maillard E, Bourhis J: Meta analysis of chemotherapy in head and neck cancer (MACH – NC); an update on 93 randomized trials and 17 346 patients. Radiother Oncol 2009; 92: 4-14.
18. Maguire PD, Meyerson MB, Neal CR et al.: Toxic cure: Hyperfractionated radiotherapy with concurrent cisplatin and fluorouracil for stage III and IVA head and neck cancer in the community. Int J Radiat Onc Biol Phys 2004; 58: 698-704.
19. Denis F, Garaud P, Bardet E et al.: Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: Comparison of the LENT/SOMA, RTOG/EORTC and NCI-CTC scoring system. Int J Radiat Oncol Biol Phys 2003; 55: 93-98.
20. Browman GP: Evidence-based recommendations against neoadjuvant chemotherapy for routine management of patients with squamous cell head and neck cancer. Cancer Invest 1994; 12: 662-671.
21. Adelstein DJ, LeBlanc M: Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and cancer? J Clin Oncol 2006; 24: 2624-2628.
22. Machtay M, Rosenthal DI, Hershock D et al.: Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal cancer: A University of Pennsylvania phase II trial. J Clin Oncol 2002; 20: 3964-3971.
23. Vokes EE, Stenson K, Rosen FR et al.: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 2003; 320-326.
24. Urba SG, Moon J, Shankar Giri PG et al.: Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: A Southwest Oncology Group trial. J Clin Oncol 2005; 23: 88-95.
25. Psyrri A, Kwong M, DiStasio S et al.: Cisplatin, fluorouracil, and leucovorin induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: Long term follow up. J Clin Oncol 2004; 22: 3061-3069.
26. Posner MR, Hershock D, Le-Lann L et al.: A phase III trial of docetaxel, cisplatin and 5-fluorouracil (TPF) versus cisplatin and 5-fluorouracil (PF) induction chemotherapy (IC) followed by chemoradiotherapy (CRT) in patients with locally advanced squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 2006; 25: 4606.
27. Robert F, Ezekiel MP, Spencer SA et al.: Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 19: 3234-3243.
28. Bonner JA, Harari PM, Giralt J et al.: Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Eng J Med 2006; 354: 567-57.
29. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-years survival data form a phase 3randomized trial, and relation between cetuximab – induced rash and survival. Lancet Oncol 2009; 11: 21-28.
30. Jacobs C, Lyman G, Velez-Garcia E et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 1257-1265.
31. Kawecki A: Ocena skuteczności i wskazań do chemioterapii chorych z nawrotami lub przerzutami odległymi w przebiegu raka narządów głowy i szyi. Nowotwory J Oncol 2001; 51 (suppl. 2): 1-61.
32. Gibson MK, Li Y, Murphy B et al.: Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaksel in advanced head and neck cancer (E1395): an intergroup trial of ECOG. J Clin Oncol 2005; 23: 3562-3567.
33. Herbst RS, Arquette M, Shin DM et al.: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5578-5587.
34. Vermorken JB, Mesia R, Rivera F et al.: Platinum based chemotherapy plus cetuximab in head and neck cancer. N Eng J Med 2008; 359: 1116-1127.
35. Mesia R, Rivera F, Kawecki A et al.: Quality of life of patients receiving platinum – based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010; March 24 (Epub ahead of print).
36. Vermorken JB, Trigo JM, Hitt R et al.: Open – label, uncontrolled multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum – based chemotherapy. J Clin Oncol 2007; 25, 2171-2177.
37. Baselga J, Trigo JM, Bourhis J et al.: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum based chemotherapy in patients with platinum – refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5568-5577.
38. Stewart JS, Cohen EE, Licitra L et al.: Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck (corrected). J Clin Oncol 2009; 27: 1864-1871.
39. Elser C, Siu LL, Winquist E et al.: Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007; 25: 3766 -3773.
40. Machiels JP, Henry S, Zanetta S et al.: Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck; GORTEC 2006-01. J Clin Oncol 2010; 28: 21-28.
41. Cohen EE, Davis DW, Harrison TG et al.: Erlotinib and bevacizumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck; a phase I/II study. Lancet Oncol 2009; 10: 247-257.
