Effectiveness of radiochemotherapy on lymph node metastases in patients with stage IV oropharyngeal cancer

Oral Oncology (2004) 40, 1007–1016

http://intl.elsevierhealth.com/journals/oron/

Effectiveness of radiochemotherapy on lymph node metastases in patients with stage IV oropharyngeal cancer Nikolay R. Sapundzhieva,1, Peter J. Barthb,2, Peter Vachac,3, ¨nnea,4, Roland Mollb,5, Rita Engenhart-Cabillicc,6, Anja A. Du Jochen A. Wernera,* a

Department of Otolaryngology, Head and Neck Surgery, Philipps University of Marburg, Deutschhausstr. 3, Marburg 35037, Germany b Institute of Pathology, Philipps University of Marburg, Baldingerstraße, Marburg 35043, Germany c Department of Radiooncology, Philipps University of Marburg, Baldingerstraße, Marburg 35043, Germany Received 21 April 2004; accepted 6 May 2004

KEYWORDS

Summary Radiochemotherapy plays a leading role in the treatment of patients with advanced squamous cell carcinomas (SCC) of the oropharynx. The aim of the present study was to estimate its effectiveness on lymph node (LN) metastases. Seventeen patients with advanced UICC stage IV oropharyngeal SCC (1 · T2, 4 · T3, 12 · T4, 2 · N1, 15 · N2) were observed prospectively. They were treated with radiochemotherapy (total radiation doses 60–70.6 Gy). One to four months after neck dissection (ND) was performed. Specimens were histologically examined for metastases according to the neck levels obtained from. Local control was achieved in 14/17 (82.4%) patients and regional––in 10/17 (58.8%) patients. Of 566 LN studied, 29 exhibited signs of involvement. Two from 29 were found in neck level I, 20/29 in II, 6/29 in III and 1/29 in IV. In 13/29 LN the metastases had completely regressed under treatment whereas 16/29 LN (7 patients) contained vital tumoral tissue.

Radiochemotherapy; Oropharyngeal cancer; Neck metastases; Squamous cell carcinoma

*

Corresponding author. Tel.: +49 6421 28 66478; fax: +49 6421 28 66367. E-mail address: [email protected] (J.A. Werner). URL: http://www.hno-marburg.de. 1 Tel.: +49 6421 28 66478; fax: +49 6421 28 66367. 2 Tel.: +49 6421 28 62465; fax: +49 6421 28 65640. 3 Tel.: +49 6421 28 62973; fax: +49 6421 28 66426. 4 Tel.: +49 6421 28 66807; fax: +49 6421 28 66367. 5 Tel.: +49 6421 28 62270; fax: +49 6421 28 65640. 6 Tel.: +49 6421 28 66433; fax: +49 6421 28 66426.



1368-8375/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2004.05.008

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The observed high incidence of vital LN metastases, which abide the radiochemotherapy, advocates further studies, concerning the value of planed ND after radiochemotherapy. c 2004 Elsevier Ltd. All rights reserved.



Introduction Of all head and neck malignancies about 12% are located in the oropharynx where the SCC type accounts for 87% of the cases.1 These tumors show a marked tendency for lymphogenic spread.2–4 On initial presentation more than the half of the patients (up to 85%) have neck metastases.4–6 The rest patients are supposed to have subclinical neck invasion in up to 40% of the cases. The high incidence of occult metastases is an important arguments in favor of the elective treatment of the neck.4–8 In treatment with curative intent the control over the neck disease is crucial for the prognosis. After the chemoradiation was accepted as an alternative to combined surgery and adjuvant radiotherapy in advanced laryngeal SCC, nowadays the application of this concepts to other head and neck SCC (HNSCC) are actively evaluated.9 In the last two decades the role of combined radiochemotherapy increases in the context of organ preservation.1,10,11 This approach proved to be effective in controlling the primary lesion in selected cases.5,12 Usually the irradiation is targeted to the primary lesion, while the neck is irradiated in an unspecific way. The local and the regional control achieved differ.10,12–14 On this background a prospective study was undertaken to evaluate the response of the regional metastases of oropharyngeal SCC to radiochemotherapy.

Materials and methods Patient selection A prospective cohort study was designed, comprising 17 patients (1 female, 16 male, 53.7 ± 7.8 years, range 40–67) with advanced oropharyngeal SCC assigned to radiochemotherapy and consecutive ND. The mean follow up was 12.5 ± 7.7 months. Patientswith previous surgical treatment of the primary, with unresectable failure at the primary or

any previous surgical interventions to the neck were excluded from the study.

Staging Staging was done according to the TNM system of the Union Internationale Centre le Cancer (UICC). The extent of the tumor was examined during panendoscopy. Biopsies wereperformed for histological verification. During the panendoscopy the borderline of the tumor was marked by tattooing, in order to allow comparison after the radiochemotherapy.

Imaging diagnosis At the time of initial presentation high resolution B-mode-sonography was performed in all patients (Acuson 128 XP/4 unit, Acuson Corporations, CA, USA, with a wide-bandwidth transducer). The LN diameters in transverse and longitudinal planes were measured. As metastasis positive were considered LN with short-axis diameter >7 mm and/or round shape (reduction in the ratio of maximal longitudinal to maximal axial diameter), unclear boundary or irregular hilar and internal echoes. In six cases fine needle aspiration (FNA) biopsy was performed. All LN metastases were photographically documented as well as their topography according to the classification of the American Academy of Otolaryngology, Head and Neck Surgery.15 All patients were subjected to computer tomography (CT) of the primary tumor and the neck. The findings were used for estimation of the depth of tumoral infiltration and the extent of regional and distant dissemination and the planning of the irradiation.

Radiochemotherapy The treatment approach was designed by a multidisciplinary tumor board. It included initial radiochemotherapy, followed by panendoscopy with laser surgical excision with in the prethera-

Effectiveness of Radiochemotherapy peutically tatoowed borders of the primary region and ND according to the extent of the pretherapeutical N-status. If appropriate, endoscopic laser surgery or opened resection of the primary region was completed.16 All patients pretherapeutically underwent dental evaluation and treatment. Cast fixation with individual masks was used for each patient. The target volume included the site of the tumor and the cervical and supraclavicular lymph node regions. For irradiation parallel opposed photon/ electron-beam portals with an anterior photon field for the lower neck and the supraclavicular lymph nodes were used. Macroscopic primary tumor and clinically positive lymph nodes had to be included in the boost volume. To reduce side effects individual blocks or multileaf-collimator were used for field shaping. Treatment was performed with 6/18 MV photons and 9–12 MeV electrons. Five patients were treated by conventional fractionated irradiation with 2 Gy single dose up to 66 Gy. Boost irradiation was applied starting after 54 Gy. After receiving 30 Gy the conventionally fractionated radiotherapy in a group of 12 patients was followed by hyperfractionated accelerated irradiation with 1.4 Gy per fraction twice a day to a total dose of 70.6 Gy. The daily interfraction interval was at least 6 h.The radiation dose the patients received averaged 68.4 ± 2.7 Gy (60–70.6). It was delivered over a mean therapy duration of 8.1 ± 2.25 weeks. All 17 patients underwent chemotherapy. The schemes included Carboplatin alone (80 mg, d1– d5 or 100 mg/m2, 1/week) in 7 patients, 5-FU (600 mg/m2 d1–d5) + Mitomycin-C (10 mg/m2, d5, d36) in 8 patients, Taxol (40 mg/m2, 1/week) alone in one, Carboplatin (1/week) + Paclitaxel (40 mg/ m2 1/week) in one. Acute side effects were evaluated according to the Common Toxicity-Crtiteria (CTC) and the RTOG criteria.

Surgery Nine ± 2.6 (7–15) weeks after the initial radiochemotherapy, a panendoscopy and laser surgical excision of the primary tumor site within the tattoo marks were done.16 Additionally, all patients underwent a planned ND 1.9 ± 0.9 (1–4) months after the end of the therapy. Seven patients had bilateral and 10 ipsilateral ND. In 20/24 neck sides modified radical ND(MRND) was performed and in 4/24 neck sides selective ND of levels I–IV (SND I–IV) was performed. During the ND special attention was given to carefully mark the obtained specimens according to their anatomical situation relative to the neck levels.

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Histopathological evaluation Tissues were fixed in an unbuffered 10% formalin solution, embedded in paraffin, serial sections of approximately 6 lm thickness were stained H & E and PAS for microscopic evaluation. Immunohisochemistry was performed according to the standard biotin avidin complex (ABC-) peroxidase method with diaminobenzidine as chromogen using a broad range cytokeratin antibody (CK MNF 116, DAKO, Hamburg, Germany). For each specimen the total number of LN was recorded together with the nodal yield from each neck region. The number of histologically metastatic and tumor free LN in each neck level was compared with the initial Nstatus. The pathological changes were classified into five grades: Grade 0––tumor-free LN without regressive signs; Grade 1––tumor-free LN with degenerative changes (hyalinosis, fibrosis); Grade 2––partial fibrinoid necrosis of the metastatic LN; Grade 3––LN with parakeratotic cells and Grade 4––vital LN metastases. Grades 2–4 were regarded as regional failures of the radiochemotherapy, because of the presence of still vital tumoral tissue. Only findings graded 0 and 1 were accepted as good regional control.

Results At initial presentation all patients had an advanced (stage IV) oropharyngeal carcinoma (11 · tonsils, 6 · base of the tongue). Most of them had an advanced T-stage (1 · T2, 4 · T3,12 · T4). In 4 patients the tumor was on the left side and in 13––on the right side. In 7 patients the tumor extended beyond the midline. After biopsy all tumor lesions were histologically determined as SCC with different stage of differentiation: well differentiated (3 · G1),moderately differentiated (11 · G2) and poorly differentiated (3 · G3). Based on the B-mode sonography and the CT scans 2 patients were staged as N1 and 15 patients––as N2 (Fig. 1). Ten patients had suspicious ipsilateral LN (2 · N1, 1 · N2a, 7 · N2b). The other 7 patients had positive lymph nodes on both sides (N2c). In 6 patients the presence of neck metastases was confirmed by FNA biopsy under sonographic quidance. More than the half of the suspected regional metastases were detected in neck level II (52.4%) Of them 86.4% were localized in level IIa and only 13.6% in IIb. Level III harbored 42.9% of the suspect metastatic LN and levels I and IV––only 2.4% each. In no patient metastases were detected in levels V or VI (Fig. 2a).

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Figure 1 Characteristics of the study cohort, based on panendoscopy, B-mode-sonography and CT. Initial T stage is presented for all 17 patients in the central circle. The band in the periphery shows the corresponding N stage. No patient had evidence of distant metastases (M0).

N.R. Sapundzhiev et al. Under radiochemotherapy the following severe complications were observed: mucositis grade II– III––5 patients, radiodermatitis grade II––3 patients, grade III––2 patients, leucopenia grade III––2 patients. In two patients a temporary treatment interruption was necessary because of side effects. The dys- and odynfagia caused by mucositis presented feeding-limiting conditions, which together with the toxic effects of the therapy led to considerable loss of weight in 6 patients. The postradiochemotherapeutical control panendoscopy and rebiopsy of the primary tumor site within the tattoo marks showed no tumor in 14/ 17 (82.4%) patients. In 3/17 cases (17.6%) there was residual tumor. Two of them became tumorfree after consecutive endoscopic laser resection. The other patient was subjected to open resection of the tumor residuum.

Figure 2 Graphical presentation of the incidence of LN metastases in the different neck levels on the ipsilateral to the tumor side and on the contralateral: (a) initial (pretherapeutic) distribution of metastatic LN and (b) pathologic LN found in ND speciment after the radiochemotherapy. Here metastatic LN which still contain viable tumor tissue are marked in black. In white the LN with complete necrosis, fibrosis or granuloma formation and no vital tumor cells (complete responders) are presented.

Effectiveness of Radiochemotherapy Table 1

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Distribution of the lymph nodes studied and those with metastatic involvement

Neck level

I

II

III

IV

V

Total number of lymph nodes dissected Total number of LN with metastatic involvement Of them histologically complete responders Vital metastases or incomplete response

42 2 0 2

169 20 11 9

128 6 1 5

95 1 1 0

132 0 0 0

In the 24 ND specimens obtained a total number of 566 (average 23.6/neck specimen) lymph nodes were found and histologicaly examined (Table 1). The specimens were marked intraoperatively by the surgeon according to the neck levels they were obtained from. Summing up all examined LN per neck level in level I 42 LN (average 1.9), in level II––169 LN (average 7.0), in level III––128 LN (average 5.3), in level IV––95 LN (average 4.1)and in level V––132 LN (average 6.0) were found. Twenty nine LN showed signs of metastatic involvement: 2 were located in level I, 20 in level II, 6 in level III and 1 in level IV (Fig. 2b). In 13/ 29 LN complete metastases regression (complete necrosis, fibrosis or granuloma) without any signs of active tumoral tissue was observed. In 16/29 there was still vital tumoral tissue. In 3 patients the highest grade for any single pathologically changed LN was grade IV, in 4––grade 3, in 5–– grade 1 and in 5––grade 0 (Fig. 3). Three LN in three patients had massive capsule disrupture with perinodal infiltration. The comparison between the initial neck status and the posttherapeutic findings showed, that radiochemotherapy had achieved good regional control in 10 patients (11 neck sides dissected). In 7 of them the local control was good too. Of the rest 3 patients 2 became tumor-free after laser surgical resection of the primary and one after opened surgery (Fig. 4). In 7 cases (8/13 neck sides dissected) the radiochemotherapy failed to achieve control, while in all of them the primary tumor region was cured. The distribution of pretherapeutically suspected lymph nodes and histologically proven metastases in the different neck levels are summarized in Table 2. The ND in these previously irradiated patients was estimated by the surgical team as relatively more difficult compared to nonirradiated ones. However this did not cause any technical limitation to the extent or the quality of the intervention. No intraoperative complications during the ND occurred, which could be partially or completely attributable to the radiochemotherapy. The only early postoperative complication was arterial

bleeding 3 h postoperatively, that necessitated reoperation and ligation of the vessel.

Discussion The therapy of advanced oropharyngeal carcinoma with curative intent should focus both on the primary tumour and on the regional LN metastases. The therapeutic results at the primary site are easily controlled with biopsy. The evaluation of the control over the neck metastases is based on different imaging techniques. The B-mode sonography––an imaging tool characterized with very high sensitivity and specificity for detecting of suspect LN––could not answer the question, whether posttherapeutically enlarged LN still harbor vital tumoral cells. Residual metastases or recurrences in the neck determine a bad overall prognosis.10,17 Their tendency to progress, causing involvement and destruction of neck structures and distant metastases, presents a decisive factor in patients, in whom the primary tumor is successfully controlled by the radiochemotherapy. On this background the objective of the present study was to evaluate the response of metastatic LNs in different neck levels to primary chemoradiation in patients with advanced oropharyngeal carcinoma.

Management of the oropharyngeal carcinoma The two therapeutic modalities targeting the primary tumor in advanced disease are surgery and radiochemotherapy. The local control achieved after surgery alone depends on the initial size of the tumor and varies between 70% and 100%.5,16,18,19 It is often at the cost of large defects, that even after reconstruction result in dysfunction. Based on the notion of organ-preservation, the radiochemotherapy is an accepted alternative to surgery with adjuvant radiotherapy for oropharyngeal carcinomas in any stage. Providing the same survival rate as surgery, they have the advantage of

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Figure 3 (a) Photomicrograph showing xanthomatous lymphadenitis with densely packed foam cells and multinucleated giant cells––Grade 1 (H&E); (b) photomicrograph of complete coagulation necrosis surrounded by multinucleated giant cells and fibrosis––Grade 1. (c) Photomicrograph of extensive tumor necrosis (upper right) with few interspersed parakeratotic cells and multinucleated giant cells––Grade 2 (H&E); (d) grade 3 lesion consisting of parakeratotic cells, necrotic tumor, multinucleated giant cells and surrounding scar tissue––Grade 3 (H&E); (e) photomicrograph of densely packed parakeratotic cells––Grade 3 (H&E); (f) photomicropgrah of squamous cell carcinoma forming small solid nests and focal necrosis––Grade 4 (lower center, H&E); (g) Immunohistchemistry highlights nests of vital tumor surrounded by a myofibroblast rich stroma––Grade 4 (CK MNF116, ABC-peroxidase) and (h) immunohistochemistry highlights solid nests of squamous cell carcinoma, the surrounding tissue is fibrotic and harbors areas of necrosis and small accumulations of parakeratotic cells––Grade 4 (CK MNF116, ABC-peroxidase).

organ-preservation.5,9,12,19–22 Specific irradiation regiments like the ipsilateral radiotherapy 12 or brachytherapy18,23 have proved their effectiveness in small studies. However, they do not target the neck and the good local results are often compromised (up to 28% in previously N0 patients) by regional failures.24 Chemotherapy alone is not

considered as curative treatment modality, but has an important modulating effect over the radiosensitivity.9,19 Simultaneously performed the (concurrent) radio- and chemotherapy is characterized by better locoregional control, but higher acute toxicity compared to radiotherapy alone, while the late toxicity does not differ.2

Effectiveness of Radiochemotherapy

Figure 4

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Local and regional control achieved by the initial RChT.

Table 2 Distribution of pretherapeutically suspected lymph nodes and histologically proven metastases in the different neck levels before and after radiochemotherapy (RC) Pat.

269 286 445 493 495 517 522 589 607 616 622 630 646 677 717 719 720

Staging

T3N2bM0 T4N2cM0 T4N2cM0 T4N2cM0 T4N2cM0 T4N2bM0 T4N2cM0 T3N2bM0 T4N2cM0 T3N2bM0 T2N2bM0 T4N2bM0 T4N2bM0 T3N2cM0 T4N2aM0 T4N1M0 T4N1M0

TU crossing the midline

Yes Yes Yes No No No Yes No Yes No No No No Yes No No Yes

Before RC

After RC

Sono and/or FNA positive neck levels ipsi

contra

IIa, III IIa IIa, III IIa, III Ib, IIb IIa IIa, III, IV IIa, III III III IIa, III IIa, III IIa, III IIa IIa III IIa

– IIa, III, IV lIb III IIa – III – IIa, IIb – – – – IIa – – –

Control of the primary TU

RC + LSR RC RC RC RC RC RC RC RC RC RC RC RC + LSR RC RC RC + LSR + OS RC

Neck levels with vital metastases ipsi

contra

– – II – II – – – III – I, II, III I, II, III – II II – –

– II, III – No ND – No ND No ND No ND – No ND – No ND No ND II No ND No ND No ND

Pathol. score

1 3 3 1 3 0 0 0 4 1 4 3 0 4 1 0 1

The tumoral stages of each patient, lateralization and position to the midline are presented. For each neck side pretherapeutical distribution of the LN metastases according to the neck levels and the histologic findings in the specimen are presented (LSR—Laser surgical resection; OS—open surgery). The pathologic score shows the highest score found in any of the examined LN for the given patient.

Approaches to the neck disease The well-known pathways of lymphatic metastatic spread to certain neck levels presen the rationale for selective ND.4,6,22,25,26 Though the small number of patients our results confirm the classical pathways of lymphogenic metastatic spread from the oropharynx. Metastases were found predominantly in level II (69% of all histologically proven metastases) and to a lesser extent in levels III and I (20.7% and 6.9%, respectively). In our cohort only one patient presented with metastases in level IV (3.5% of all histologically proven metastases).

Chemoradiation shows a relatively lower effectiveness in managing the neck disease. LN metastases are radiosensitive, but we can not precise the dose, required to sterilize them. In the majority of the studied neck specimens necrosis or partial sclerosis and fibrosis and hyalinosis of the LN was observed. These findings correspond to metastases cured by the irradiation.27 In our study such findings were observed in 10 patients (13 from 29 involved LN) and were interpreted as good regional control. The target of the radiation is the cell DNA. Histologically vital tumor cells might have irreversible DNA damage resulting in apoptosis or decay of the capacity to proliferate. So the effect of

1014 irradiation should be judged not immediately after its end, but after a period of time corresponding to several mitotic cycles. In our study the interval from the end of the initial therapy to the ND is 1.9 ± 0.9 (1–4) months. We assume, that vital tumoral cells detected at this time are obviously not sterilized by the radiation and capable of further proliferation. Irradiation does not lead to significant reduction of the number of the lymphatic vessels in the target region. Beam energy causes only transitory changes in the permeability of their endothelial lining.4,28 Obviously any time during the radiotherapy metastases from the tumor or secondary metastases from the LN could propagate. Any treatment of the neck could modify the common pathways of lymphatic drainage leading to metastases in unusual sites.4,29 In the study of Mabanta et al.17 15% of the neck recurrences occur at levels initially without metastases. We found metastatic lymph nodes at pretherapeutically free levels in 2/17 patients, in both cases to level I. Probable explanations for this include: (A) underdiagnosis at start/ micrometastases with undetectable size; (B) continuous spread from the primary tumor; (C) secondarily spread from neck metastases; (D) modification of the common pathways for lymphatic drainage under the irradiation.8,28,30

Failures and recurrences after primary radiochemotherapy with curative intent The clinical estimation of the neck response to chemoradiation is often unreliable.10 Of the imaging methods CT, sonography and MR imaging come in consideration. CT is a widely accepted standard for its sensitiveness and reproducibility.31 The sonography has the advantage of being inexpensive and little resource- and time-consuming. In experienced hands this technique shows superior to CT.24,32 Nevertheless small metastases often remain undetected, which could explain the early neck recurrences. Several studies examined ND specimens in groups of ‘‘complete responders’’. In their patient collective Lavertu et al.10 observed 29% residual neck disease after chemoradiation. Viable tumor was found in 25% of the complete responders to radiochemotherapy and in 50% of those with lymphadenopathy after treatment. Peters et al.8 reported 15% initial neck failures. McHam et al.13 found pathologic evidence of disease in one quarter of the patients with complete clinical response. In our cohort at the time of posttherapeutic estimation of the neck (range 1–4 months) residual partially or completely viable

N.R. Sapundzhiev et al. metastases in ND specimens were found in 7/17 patients (41.2%). Explanations for this larger number include the primary localization (only patients with oropharyngeal cancer whereas the other studies report generally on head and neck cancer) and the initially advanced stage. As recurrences should be regarded neck metastases appearing in complete responders after a considerable period of time. In patients with both local and regional recurrences the neck failure seldom present after the one at the primary site, which indicates the marked independence of the metastasis as an autonomic tumor.22,28 The reported incidence of neck recurrences after primary radiotherapy for oropharyngeal cancer patients with positive neck disease varies from 8% to 20%.5,8,10,17,33 Mabanta et al.17 reported 40% of the neck recurrences after irradiation to occur in patients with complete and 60% in ones with incomplete clinical regression of the adenopathy. Peters et al.8 reported relatively smaller figures – regional recurrences may develop in complete responders to irradiation in up to 7% within 2 years. Both studies report neck recurrences to occur more often than those at the primary site. Because of the short follow up of our patients and the small cohort a report on recurrences would be unprecise at the present. When planning irradiation, more care should be paid to already present metastases, as well as to the primary region specific neck levels. A higher transient radiation dose through fields lying over such lymph node groups, or complementary boost in these levels could eventually improve the control.34 Given the low effectiveness of the standard regiments for radiochemotherapy on the neck disease, elective surgical exploration seems a reasonable approach in any pretherapeutical N > 0 case. For the complete responders the ‘‘wait and see’’ approach is widely accepted. Here the disadvantage is the low sensitivity of the methods for neck observation for micrometastases. The best diagnostic, staging and partially curative procedure would be SND. Based on the notion of predominance of the lymphatic spread from a given primary to certain neck levels and some new radiological techniques an even more selective approach, namely the sentinel lymph node biopsy, was advocated lately for head and neck SCC.35 It is not clear to which extent these two concepts are still applicable in patients after initial irradiation. Here a modification of the lymphatic network of the neck could be expected and the incidence of metastases to untypical levels is relatively high.22,28 That is why, in such patients we tend to perform MRND. The approach to patients with no response or even

Effectiveness of Radiochemotherapy propagation of the neck disease under chemoradiation should be more aggressive––interruption of the regiment and early elective salvage with (M)RND.

Conclusion Surgery with adjuvant radiotherapy and primary radiochemotherapy are alternative treatment modalities for the primary tumor in advanced cancer of the oropharynx. The selection of primary treatment modality depends to a big extent on the routine practice of every tumor board. In the last decades there is a clear trend towards organ preservation with radiochemotherapy. Of the 17 patients followed in this study the chemoradiation failed as only treatment in 10 (58.8%)––in 3 (17.6%) at the primary site only, in 7 (41.2%) in the neck only. We did not observe failures at both primary site and neck in any of our patients. Our results show, that the effectiveness of this approach could be significantly improved by surgical treatment of the neck and the primary site. After primary chemoradiation, recurrences may appear in untypical for the primary neck levels. All pretherapeutical N > 0 patients could be considered candidates for elective ND with some regard to the response to the initial therapy regiment. The neck status should be closely monitored during the radiochemotherapy.17,32 If the neck disease does not respond to the treatment or even progresses ND should be performed immediately as a salvage procedure. The value of the sonographic monitoring of the neck status during chemoradiation needs further evaluation.

References 1. Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:951–62. 2. Staar S, Rudat V, Stuetzer H et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy––results of a multicentric randomized German trial in advanced head-andneck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161–71. 3. Petruzzelli GJ. The biology of tumor invasion, angiogenesis and lymph node metastasis. ORL J Otorhinolaryngol Relat Spec 2000;62:178–85. 4. Werner J. Aktueller Stand der Versorgung des Lymphabflusses maligner Kopf-Hals-Tumoren. Eur Arch Otorhinolaryngol(Suppl. 1):47–85. 5. Jones AS, Beasley NJ, Houghton DJ, Williams S, Husband DG. Treatment of oropharyngeal carcinoma by irradiation or by surgery. Clin Otolaryngol 1998;23:172–6.

1015 6. Wong RJ, Rinaldo A, Ferlito A, Shah JP. Occult cervical metastasis in head and neck cancer and its impact on therapy. Acta Otolaryngol 2002;122:107–14. 7. Beer K, Greiner R, Aebersold D, Zbaren P. Carcinoma of the oropharynx: local failure as the decisive parameter for distant metastases and survival. Strahlenther Onkol 2000;176:16–21. 8. Peters LJ, Weber RS, Morrison WH, Byers RM, Garden AS, Goepfert H. Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy. Head Neck 1996;18:552–9. 9. Wolf GT, Forastiere A, Ang K et al. Workshop report: organ preservation strategies in advanced head and neck cancer––current status and future directions. Head Neck 1999;21:689–93. 10. Lavertu P, Adelstein DJ, Saxton JP et al. Aggressive concurrent chemoradiotherapy for squamous cell head and neck cancer: an 8-year single-institution experience. Arch Otolaryngol Head Neck Surg 1999;125:142–8. 11. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949–55. 12. OÕSullivan B, Warde P, Grice B et al. The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 2001;51:332–43. 13. McHam SA, Adelstein DJ, Rybicki LA et al. Who merits a neck dissection after definitive chemoradiotherapy for N2– N3 squamous cell head and neck cancer. Head Neck 2003;25:791–8. 14. Yueh B, Feinstein AR, Weaver EM, Sasaki CT, Concato J. Prognostic staging system for recurrent, persistent, and second primary cancers of the oral cavity andoropharynx. Arch Otolaryngol Head Neck Surg 1998;124:975–81. 15. Robbins KT, Medina JE, Wolfe GT, Levine PA, Sessions RB, Pruet CW. Standardizing neck dissection terminology. Official report of the AcademyÕs Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck Surg 1991;117:601–5. 16. Werner JA, Dunne AA, Folz BJ, Lippert BM. Transoral laser microsurgery in carcinomas of the oral cavity, pharynx, and larynx. Cancer Control 2002;9:379–86. 17. Mabanta S, Mendenhall W, Stringer S, Cassisi N. Salvage treatment for neck recurnce after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck 1999;21:591–4. 18. Gourin CG, Johnson JT. Surgical treatment of squamous cell carcinoma of the base of tongue. Head Neck 2001;23:653–60. 19. Clayman GL, Johnson 2nd CJ, Morrison W, Ginsberg L, Lippman SM. The role of neck dissection after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease. Arch Otolaryngol Head Neck Surg 2001;127:135–9. 20. Poulsen MG, Denham JW, Peters LJ et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study. Radiother Oncol 2001;60:113–22. 21. Fallai C, Olmi P, Cellai E. Advanced carcinomas of the oropharynx treated with radiotherapy––a comparison of three different fractionation schemes. Am J Otolaryngol 1993;14:31–7. 22. Doweck I, Robbins KT, Mendenhall WM, Hinerman RW, Morris C, Amdur R. Neck level-specific nodal metastases in

1016

23.

24.

25.

26.

27.

28.

oropharyngeal cancer: is there a role for selective neck dissection after definitive radiation therapy. Head Neck 2003;25:960–7. Puthawala A, Nisar Syed AM, Gamie S, Chen YJ, Londrc A, Nixon V. Interstitial low-dose-rate brachytherapy as a salvage treatment for recurrent head-and-neck cancers: long-term results. Int J Radiat Oncol Biol Phys 2001;51:354–62. Yuasa K, Kawazu T, Kunitake N et al. Sonography for the detection of cervical lymph node metastases among patients with tongue cancer: criteria for early detection and assessment of follow-up examination intervals. AJNR Am J Neuroradiol 2000;21:1127–32. Werner J. Historischer Abriss zur Nomenklatur der Halslymphknoten als Grundlage fur die Klassifikation der Neckdissection. Laryngorhinootologie 2001;80:400–9. Werner JA, Dunne AA, Myers JN. Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract and its role in metastasis of squamous cell carcinoma. Head Neck 2003;25:322–32. Westra W, Forastiere A, Eisele D, Lee D. Squamous cell granulomas of the neck: histologic regression of metastatic squamous cell carcinoma following chemotherapy and/or radiotherapy. Head Neck 1998;20:515–21. Lang J. Erkrankungen des zervikalen Lymphsystems. In: Naumann H, editor. Oto-Rhino-Laryngologie in Klinik und Praxis. Stuttgart: Thieme; 1995. p. 156–79.

N.R. Sapundzhiev et al. 29. Robson A. The management of the neck in squamous head and neck cancer. Clin Otolaiyngol 2001;26:157–61. 30. Ossoff RH, Sisson GA. Lymphatics of the floor of the mouth and neck: anatomical studies related to contralateral drainage pathways. Laryngoscope 1981;91:1847–50. 31. Ojiri H, Mendenhall W, Stringer S, Johnson P, Mancuso A. Post-RT CT results as a predictive model for the necessity of planned post-RT neck dissection in patients with cervical metastatic disease from squamous cell carcinoma. Int J Radiation Oncology Biol Phys 2002;52:420–8. 32. Sumi M, Ohki M, Nakamura T. Comparison of Sonography and CT for differentiating benign from malignant cervical lymph nodes in patients with squamous cell carcinoma of the head and neck. Am J Radiol 2001;178:1019–24. 33. Kokemuller H, Brachvogel P, Eckardt A, Hausamen J. Effektivitat der neck dissection beim metastasierenden mundhohlenkarzinom: uni- und multivariate analyse von einflussfaktoren. Mund Kiefer Gesichtschir 2002;6: 91–7. 34. Clifford CK, Wippold F, Ozyigit G, Tran B, Dempsey J. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients, receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53:1174–84. 35. Werner J, Dunne A, Ramaswamy A et al. Sentinel node detection inN0 cancer of the pharynx and larynx. Br J Cancer 2002;87:711–5.