CLINICAL REVIEW

David W. Eisele, MD, Section Editor

INDICATIONS FOR RADIOTHERAPY AFTER NECK DISSECTION

Primoz Strojan, MD,1 Alo Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,2 Johannes A. Langendijk, MD, PhD,3 Carl E. Silver, MD4
1 2

Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy. E-mail: a.ferlito@uniud.it 3 Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 4 Departments of Surgery and OtolaryngologyHead and Neck Surgery, Albert Einstein College of Medicine, Monteore Medical Center, Bronx, New York

Accepted 29 July 2010 Published online 10 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21599

Abstract: Up-front surgery and postoperative radiotherapy constitute a well-recognized treatment concept for locally or regionally advanced squamous cell carcinoma of the head and neck. This treatment package is further intensied with the concomitant application of chemotherapy during irradiation when high-risk features (ie, microscopically involved resection margins, extracapsular extension of the tumor from neck nodes, the presence of soft tissue deposits) are found on histopathologic examination of a resected specimen. With regard to neck disease, however, the demarcation line between lowand higher-risk clinical situations, which would differ with respect to the need for postoperative radiotherapy, is not clear. In an attempt to dene the low-risk characteristics of disease in the neck that do not require adjuvant irradiation, we reviewed the available literature reports for any direct or indirect evidence on the value of postoperative radiotherapy in various clinical scenarios. The number of positive lymph nodes found in a dissected tissue specimen that should be used as a cut-off point for introduction of postoperative radiotherapy was evaluated in the context of both primary tumor characterisC tics and type of neck dissection. V 2010 Wiley Periodicals, Inc. Head Neck 34: 113119, 2012 Keywords: neck dissection; postoperative radiotherapy; squamous cell carcinoma; head and neck; regional control

Several retrospective studies have persuasively conrmed that the combination of initial surgery and postoperative radiotherapy (PORT) yields signicantly improved rates of locoregional tumor control as well as an overall survival benet in squamous cell carcinoma of the head and neck (SCCHN).1 The concept of a multimodal approach in the treatment of the primary tumor and neck has gained wide acceptance
Correspondence to: A. Ferlito This article was written by members of the International Head and Neck Scientic Group.
C V 2010 Wiley Periodicals, Inc.

and has become a well-recognized pattern of practice in head and neck oncology. Considerable efforts have been invested in exploring the indications for combined therapy. In 2 phase III cooperative randomized trials conducted in Europe and the United States,2,3 extracapsular extension (ECE) of nodal disease and the presence of tumor at the surgical margins were identied as the most detrimental prognostic indicators for locoregional control and disease-free survival, justifying intensication of PORT with the addition of concomitantly applied chemotherapy.4 In practice, the same applies to the soft tissue deposits in the neck other than those recognized as ECE. These deposits may represent clusters of metastatic tumor cells from completely destructed lymph node, without any residual lymphatic tissue visible at histopathologic examination or, alternatively, they may represent tumor emboli within the vascular system that became lodged in a lymphatic or vascular space and continued to grow there.5 Although supported by less evidence, adjuvant chemoradiation protocols seem to yield a gain when other disease characteristics, that put the patient at increased risk for disease reappearance, are present. These include stage III or stage IV disease, perineural inltration, vascular embolisms, and involvement of level IV or level V nodal basins in patients with oral cavity or oropharynx primary tumors without ECE or a positive margin. Conversely, the risk level in patients with !2 positive lymph nodes without capsular penetration and with adequate surgical margins seems to be only modest and does not present an indication for concomitant chemotherapy.4 Other studies have provided data on risk-level stratication, which are generally complementary to the results of the aforementioned analyses,613 although it was suggested that the prognostic importance of individual prognostic markers may vary across different tumor sites in the head and neck.14

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At the other end of the risk spectrum, the demarcation line between low-risk clinical scenarios requiring only 1 treatment modality (ie, surgery or radiotherapy) and those with higher risk, which should be managed by a combined approach, is not clearly dened. In the present report, we review the existing evidence on the use of PORT against surgery alone in the lower-risk setting, limiting the discussion and conclusions to neck disease. The number of positive lymph nodes found in a dissected tissue specimen that should be used as a decision-making criterion for the introduction of PORT is discussed and evaluated in the context of both primary tumor characteristics and type of neck dissection.
STATUS OF NODAL DISEASE PORT for Multiple Positive Neck Nodes. The concept of combined treatment in SCCHN evolved empirically, as did the indications for PORT. On the basis of these developments, in 1992 Peters et al15 at MD Anderson Cancer Center reported on a scoring system for assessment of risk for recurrence in the neck after previous surgery (and a separate one for the primary tumor). The criteria used for categorizing patients into different risk groups in this system were based on the authors best estimate of the relative importance of different clinicopathologic factors in disease control above the clavicles, as documented in reports of surgical series. For the neck, they recognized 5 criteria: number of involved nodes and nodal groups, size of the largest positive node, ECE, and invasion of neighboring structures. Analysis of prognostic factors predictive of locoregional recurrence showed that the only variable of independent signicance was extracapsular nodal disease. However, clusters of 2 or more of the following putative risk factors were associated with a progressively increased risk of recurrence: oral cavity primary, mucosal margins close or positive, nerve invasion, !2 positive lymph nodes, largest node >3 cm, treatment delay >6 weeks, and Zubrod performance status !2. The results of a subsequent study on PORT from the same institution were reported by Ang et al.8 Of the 213 patients with SCCHN included, they identied 31 who had no adverse pathologic factors with regard to neck disease as characterized by Peters et al,15 ie, with only 1 positive node <3 cm in maximal diameter and without ECE found in their dissected tissue specimens. This group received no PORT and at 5 years the actuarial locoregional control achieved with surgery alone was comparable to that observed in patients from the intermediate-risk group (patients with 1 adverse feature other than ECE) who received 57.6 Gy PORT, and was signicantly superior compared with the high-risk group (ECE or !2 other adverse factors) treated with 63 Gy PORT: 90% versus 94% versus 68%, respectively (p .003).

There are several other reports supporting the criteria developed in the studies from the MD Anderson Cancer Center for identication of high-risk disease that should be treated with a combined approach. In 1982, Snow et al16 reported virtually no difference in neck recurrence-free rates between pN0 (n 76) and pN1 (n 81) patients with SCCHN with no ECE treated solely with radical neck dissection. More than 90% of patients in both groups were free of neck recurrence at 5 years. These patients represented a subset of 405 patients treated from 1960 to 1970. Similarly, in 1985 DeSanto et al17 found no difference in recurrence in the neck at 2 years between 33 irradiated (23%) and 187 nonirradiated patients (20%) with pN1 disease (ECE status not specied) who underwent modied radical neck dissection between 1970 and 1980. In 1987, OBrien et al18 described treatment results in a group of 98 modied radical neck dissections performed in 86 patients with SCCHN. Among 12 patients with 1 histologically positive lymph node, only 1 recurrence occurred in the ipsilateral neck; ECE was also present in that patient. However, no difference in ipsilateral neck failure rates was observed in OBriens series between irradiated and nonirradiated patients with positive nodes (4/22 vs 4/16), although patients in the former group tended to have more aggressive disease. Moreover, in 10 pN1 and ECE-negative patients, Medina and Byers19 found only 1 recurrence within the dissected side of the neck after supraomohyoid dissection compared with 0/8 in the postoperatively irradiated group. When multiple positive nodes or ECE were recorded in the dissected specimen, adjuvant radiotherapy reduced the neck recurrence rate from 24% of patients (5/21) to 15% of patients (6/41). Likewise, Traynor et al20 reported no neck failure in 11 pN1 patients who underwent selective neck dissection; however, no details on ECE or, subsequently, on the use of PORT, which was implemented in such cases, were provided for these patients. In 1996, Barzan and Talamini21 reported on a series of 705 patients who underwent a total of 1097 neck dissections from 1976 to 1993. Briey, all but those with clinically N0 neck and laryngeal or hypopharyngeal primary tumors, who had selective dissections, underwent comprehensive neck dissection. Only patients with >2 positive nodes without capsular rupture and those with ECE, irrespective of the number of involved neck nodes, were also irradiated postoperatively. Among 120 patients with pN1 and ECE-negative disease, the regional recurrence rate was only 6.7%. In multivariate analysis, an overall number of positive nodes of >1 was predictive of a higher nodal recurrence rate. The authors concluded that a multidisciplinary approach might be suggested for !2 node positive neck disease. In a more homogeneous group with regard to the primary tumor site and stage of the disease, Wolfensberger et al22 found surgery alone an adequate treatment for early-stage squamous cell carcinoma (SCC)

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of the oral cavity (pT12) with a maximum of 1 lymph node involved (pN01) and no capsular rupture, provided that the resection margins were free of tumor. Only 3 ipsilateral neck recurrences appeared in 72 patients who had neck dissection, whereas in 11 patients with bilateral neck surgery, and in those 85 not treated contralaterally, the number of contralateral neck failures was 0 and just 2, respectively. In an unknown primary tumor setting, several authors have emphasized that there is no need for PORT when 1 neck node is inltrated with tumor cells and there is no ECE present. Coster et al23 reported a dissected neck recurrence rate of 15% of patients (2/13, 4 cases with ECE) and 25% of patients (1/4, 2 cases with ECE) for pN1 and pN2a disease, respectively. In a series of 82 patients reviewed by Iganej et al,24 25 patients were diagnosed with pN1/ pN2a disease without ECE. Ultimate tumor control above the clavicles was 81% in surgically treated patients (13/16) and was 89% for patients (8/9) treated by a combined approach. Furthermore, none of the 5 patients with pN1 disease reported by Patel et al25 experienced neck recurrence, even though 4 of those patients had undergone a single-modality approach and only the one with ECE received PORT. In 2008, more selective criteria for PORT were used by Gourin et al.26 In 337 patients with clinically N0-staged SCCHN who underwent elective neck dissection, PORT was administered when !3 nodes were found inltrated with tumor cells pathologically, as well as to patients with involvement of multiple neck levels, ECE, and adverse pathologic primary tumor features (76% of patients overall). The use of PORT was signicantly associated with improved diseasefree survival (p < .0001) and regional control at 5 years (p .0014) only when !3 nodes were involved, but not in patients with <3 positive nodes. It should be noted that a subgroup of patients without ECE, the most powerful negative prognostic indicator, was not analyzed separately. In 2000, Hosal et al27 reported regional recurrence rates after 300 selective neck dissections in 210 patients, clinically classied N0, for pathologically nodenegative and node-positive necks without ECE of 3% and 4%, respectively. However, the regional failure rate was only 2% in 58 necks with up to 2 positive nodes, whereas 2/4 necks containing >2 positive nodes failed regionally. It is worth noting here that no distinction was made between ECE-negative and -positive cases in the later analysis. The authors concluded that ECE and multiple nodal involvement should be considered markers of the biological aggressiveness of the disease and used to identify patients at high risk of recurrence, requiring adjuvant therapy. Favorable experience with PORT used for similar indications (ie, !3 positive nodes and ECE) was also reported by Chepeha et al28 in a group of 52 patients with SCCHN who had 58 selective neck dissections with at least 1 positive node of 3 cm found in a tis-

sue specimen. In addition, the use of PORT in a pN1 setting was not supported by the results presented by Schmitz et al.29 In a subset of 39 patients (of 163 patients with 281 selective neck dissection procedures), regional control rates in patients who were postoperatively irradiated (2/21) or treated solely with surgery (1/18) were 9.5% and 5.5%, respectively, although the data were not specied with regard to ECE status. The adverse impact of a high number of positive nodes (4 against 13) on neck control was conrmed with multivariate analysis by Olsen et al30 in a large retrospective review of 284 patients with pN12 neck disease treated solely with surgery. ECE was recorded in 120 of 144 patients for whom this characteristic could be determined. However, because of the rather poor neck recurrence-free survival in the pN1 group (76% at 5 years), this study theoretically supports setting the criterion for implementation of PORT all the way down to a single positive node.

Several studies suggested that the presence of a single positive node in a neck dissection specimen already warrants PORT. In this case, in particular, the presented evidence must be considered along with the type of neck dissection performed. In 1990, Leemans et al31 reported on the efcacy of treatment of metastatic neck nodes relative to the histopathologic ndings of 565 comprehensive neck dissection specimens in a series of 495 patients with SCCHN. They received PORT when !3 positive nodes or ECE were found in the specimen. Because no difference in the neck recurrence-free survival was observed between nonirradiated patients with 1 to 2 histologically positive nodes without ECE and other patient groups that did receive adjuvant radiotherapy, the authors were prompted to consider giving PORT to every patient with histologically positive nodes, irrespective of their number or ECE status. In 1996, Spiro et al32 reported on 287 patients with predominantly oral cavity primaries (in 82%) treated with supraomohyoid neck dissection. PORT was administered to all patients who were found to have metastases in cervical lymph nodes on pathologic examination; virtually the same incidence of neck failure was recorded in pN0 necks (5%) and pNpositive necks (7%). Likewise, analyzing a group of 363 patients with SCCHN who underwent 517 selective neck dissections, Byers et al33 found the regional recurrence rate in the dissected eld reduced roughly by half when PORT was used, and advised the use of PORT for all cases with even a single node found to be invaded with cancer, irrespective of ECE status. Specically in the pN1 setting with or without ECE, neck recurrence rates for irradiated and nonirradiated patients were 5.6% and 35.7% (12/36 vs 5/14, p .0137), respectively.
PORT for Pathologic N1 Neck.

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In the 1990s, the Brazilian Head and Neck Cancer Study Group34 conducted a prospective randomized study of elective modied radical versus supraomohyoid neck dissection in cT24N0 oral cavity SCCs. In that study, PORT was implemented for pathologically classied !N1 necks. The prevalence of ipsilateral neck recurrences was 12% and was 5% in the nondissected contralateral side, with no difference between the 2 treatment groups. No details with regard to the neck failure rates were provided for pN0 and pN cases. More indicative were the results reported by Kolli et al,35 who evaluated treatment outcomes in 69 patients with SCCHN, who underwent 84 supraomohyoid neck dissections. Although there was no statistically signicant difference in neck failure rates in a subset of 15 patients with pN1 disease (but unspecied ECE status) when irradiated and nonirradiated groups were compared (1/5 vs 4/10, p .35), a recurrence rate of 40% in the neck after surgery without PORT made the authors hesitant to advocate surgery alone in patients with pN1 disease. Yet, the favorable effect of adjuvant radiotherapy on regional control in 20 patients with pN2 disease was highly signicant (1/15 vs 4/5, p .005). A comparable conclusion was presented by Schiff et al,36 who reviewed a series of 220 patients with SCC of the oral tongue. In a cohort of 50 patients with pN1 neck disease, 47 underwent selective neck dissection; 40 patients did not have ECE. In a comparison of patients who received PORT with those only observed, 0/17 and 2/23 patients (p .32), respectively, experienced ipsilateral regional recurrences. The authors concluded that patients with pN1 disease without ECE may also benet from PORT. Extensive evaluation of efcacy of selective node dissection in elective and therapeutic treatment of the neck in 503 patients with SCCHN undergoing 711 procedures was reported by Ambrosch et al.37 A trend was observed toward an improved 3-year neck recurrence rate in postoperatively irradiated patients with pN1 necks (3% vs 6.3% for surgery only) and distinctly improved regional control for pN2 disease (7% vs 24%). As many as 82% of patients with ECE had PORT. The value of PORT in patients with SCCHN with pN1 disease without ECE was addressed by Jackel et al38 in 2008. The authors conducted a detailed analysis of 167 neck dissections (165 were of selective type) performed in 118 patients, of whom 46 patients (39%) received PORT and 22/46 patients also received concurrent platinum-based chemotherapy. Altogether, 8 isolated nodal failures occurred: 1 of 46 patients from the combined-therapy group and 7 of 72 patients who had surgery alone. In the latter group, 4 of the regional failures occurred in contralateral necks, of which 3 were not previously dissected. The 3-year neck recurrence rate for nonirradiated and irradiated patients was 11.2% and 2.9% (p .0921), respectively. PORT exerted no effect at all with regard to overall survival. The same results were observed when

patients with pT1 and pT2 disease, to whom adjuvant radiotherapy would normally not be recommended, were analyzed. In 2010, Chen et al39 retrospectively reviewed a homogeneous group of 59 patients with SCC of the oral tongue with pathologic T12N1 disease. These patients were treated with wide excision of the tongue primary tumor and selective or modied neck dissection, in accordance with the clinical status of the neck. In 28 patients, PORT was administered, whereas the others were only observed. Neck recurrence was diagnosed in 7/31 patients (22.6%) and 2/28 patients (7.1%) observed and postoperatively irradiated patients, respectively, and tended to occur later in the group with PORT (18 vs 14 months). Furthermore, in the observed patients all 7 regional recurrences occurred in the ipsilateral neck, whereas in the PORT group both regional failures appeared in the contralateral neck. On multivariate analysis, only PORT (hazard ratio [HR] 0.17, p .01) and ECE (HR 7.56, p .03) were signicant predictors of disease-free survival. To explore the effect of PORT in pN1 disease in more details, patients with ECE, positive margins, and lymphovascular or perineural invasion were excluded, leaving 20 patients who received and 19 who did not receive PORT for comparison. The 5-year disease-free survival rates in the 2 groups were 95% and 54.7% (p .019), respectively, and overall survival rates of 92.5% and 54.9% (p .015), respectively. The authors concluded that the presence of even a single lymph node metastasis may be indicative of more aggressive tumor behavior, which makes the tumor more difcult to control. In 2008, extensive analysis of the SEER (Surveillance, Epidemiology, and End Results) database has conrmed the benecial effect of PORT of an approximately 10% absolute increase in 5-year cancer-specic survival and overall survival for patients with lymph node positive SCCHN compared with surgery alone.40 More detailed analysis revealed that node-positive patients benet from PORT, irrespective of the site of the primary tumor (oropharynx, hypopharynx, larynx, or oral cavity) or the nodal stage. At all nodal stages, including pN1, PORT appeared superior to surgery alone.41 In 2010, in early SCC of the oral cavity, the impact of PORT in the pN1 setting was questioned in a recent study by Shrime et al.42 In a group of 1539 patients with pT12N1 classications identied in the SEER database, PORT was associated with statistically signicant improved cause-specic and overall survival in the T2 subset, most strongly in the oral tongue and the oor of the mouth.

Conclusions Regarding Indications for PORT in the pN1 Neck. A perusal of the preceding 2 subsec-

tions indicates discrepancies in conclusions of individual studies regarding the indication for PORT, particularly in patients with minimal cervical node

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involvement. In this respect, it is noteworthy that multiple factors may differ among neck dissection specimens classied as pN1. These include number of dissected nodes, presence of ECE, and size of the positive node. Furthermore, the studies cited differ in the criteria used for PORT in pN1 necks, as well as a variety of other factors that may produce selection bias. With regard to the latter issue, the level of evidence produced by the particular study is based on its design and is of paramount importance. Randomized prospective studies would produce the highest quality of evidence, but despite the length of time that PORT after neck dissection has been in use, such studies are lacking. A meticulous review of the studies cited earlier would lead, despite occasional discrepancies, to the conclusion that !2 positive nodes and the presence of ECE are adverse prognostic factors that are counteracted favorably by the addition of PORT to the treatment regimen. However, it is not clear from these studies whether ECE is an independent variable, or whether it tends to occur mostly in association with multiple node metastases. Metastases of !3 cm in size are classied N2 or higher, where there is far less dispute as to the indication for PORT.

Characteristics of the Primary Tumor. Well-recognized indications for PORT related to the characteristics of the primary tumor as determined at histopathologic examination of a resected tissue specimen are positive (<1 mm) or close (<5 mm) surgical margins, perineural tumor spread, vascular emboli, and tumor size.1,4 With the exception of the last, these factors specically increase the risk for local tumor reappearance and requests for adjuvant irradiation of the primary tumor bed only. However, in an attempt to adequately irradiate all tissue(s) at risk for tumor cell residues around the resected primary tumor, and taking into account all possible uncertainties, including movements of different origin and the physical characteristics of photon beams, irradiation portals designed to target the primary tumor bed usually cover at least the adjacent lymph node region(s) on the neck. However, the recent introduction of highly conformational intensity-modulated radiation therapy with image guidance to further improve precision of targeting of predened tissue volume might substantially reduce this effect, although not completely. Because the pattern of lymphatic drainage in the neck is rather predictable, lymph node groups irradiated in conjunction with the primary tumor are, as a rule, those with the highest probability for harboring occult metastases. To the contrary, the size of the primary tumor per se determines the frequency of neck node metastases, with the distribution pattern in the neck characterized by its site of origin. It is generally accepted that in clinical scenarios with an estimated risk of occult

lymph node metastases exceeding 20%, elective treatment to the neck, whether up-front surgery or radiotherapy, is indicated43; however, other authors have suggested that this threshold be lowered to 15%.44,45 Incidence gures based on the results of clinical recognition of the palpable cervical metastases reported by Lindberg46 and supplemented by data from a large series of neck dissection specimens were summarized by Medina.47 Accordingly, because of the propensity to metastasize to the lymph nodes of >20%, treatment of a clinically negative neck is warranted for all but T1 tumors of the oral cavity, whereas for glottic tumors, the neck should be treated only in T4-classied lesions. However, all patients with primary tumors arising in the oropharynx, hypopharyx, or supraglottic larynx should have their necks treated electively. Both surgery and irradiation are effective in this setting.48,49 The decision as to which to use is usually driven by the treatment of the primary lesion. In this regard, there might be some exceptions. First, in patients with well-lateralized tumors without pathologically involved nodes, the target volume of subsequent radiotherapy can be conned to the ipsilateral neck. In the recent study by Vergeer et al,50 the untreated contralateral neck control at 5 years after surgery (of the ipsilateral neck only in 83% of patients) and unilateral PORT was 99% and 88% for pN0 and pN12a cases, respectively, and was 73% for N2b cases. To the opposite, the question as to whether the PORT target volume can be conned to the primary site only remains to be answered, although it could be suitable in well-selected cases, such as for those with pathologically N0 ipsilateral necks. For successful treatment of disease in the neck, 2 additional factors, besides its pathohistologically determined characteristics, are of importance: the extent of neck dissection and the quality of the performed surgery. Whereas selective neck dissection is considered an appropriate option in a clinically negative neck when compared with a more comprehensive surgical procedure,33,48,51 in the case of clinically positive node(s), the available evidence on the adequacy of limited neck surgery does not allow a clear answer.49 Typically, in N0-classied oral cavity primaries, metastases, when found pathologically, are located in regions IIII, whereas those from oropharyngeal, hypopharyngeal, and laryngeal SCCHN tend to appear along the jugular chain, ie, in regions IIIV. No difference in the distribution pattern of metastases in the neck was observed between patients who underwent elective and therapeutic neck dissections; however, spread of the disease into an extra level (or levels) was noticed in patients with clinically positive nodes.52,53 Furthermore, whereas the phenomenon of skip metastases, bypassing the orderly pattern of progression in the neck, is not commonly observed in SCCHN, in tumors originating in the oral cavity, the
Extent of Neck Surgery.

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reported incidence of skip metastases reached 15.8%.54,55 Thus, the high neck-control rates for subclinical disease achieved after administration of elective radiotherapy in patients with clinically classied N0 disease48 intuitively leads clinicians to implement PORT if they do not feel comfortable with the extent of the performed surgical procedure, when either the type of dissection or the thoroughness of the clearance of individual neck compartments is in question. In practice, this results in more frequent implementation of PORT in patients who have undergone more limited regional dissection, even though the disease burden described at the histopathologic examination would be comparable to that found after comprehensive neck dissection. However, the corrective potential of PORT, which allows clinicians to compensate for eventually insufcient surgery in a low-risk setting when compared with adequate neck dissection, was not evaluated in a prospective manner.
CONCLUSIONS

study objectives. Because the aim of the authors is to provide a basis for general treatment recommendations, which are currently lacking in this subset of patients with SCCHN, results are eagerly awaited.

REFERENCES
1. Langendijk JA, Ferlito A, Takes RP, et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. Oral Oncol 2010;48:577585. 2. 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. 3. 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. 4. Bernier J, Cooper JS, Pajak TF, et al. Dening 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: 843850. 5. Jose J, Ferlito A, Rodrigo JP, Devaney KO, Rinaldo A, MacLennan K. Soft tissue deposits from head and neck cancer: an under-recognised prognostic factor? J Laryngol Otol 2007; 121:11151117 (editorial). 6. Amdur RJ, Parsons JT, Mendenhall WM, Million RR, Stringer SP, Cassisi NJ. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int J Radiat Oncol Biol Phys 1989;16:2536. 7. Cooper JS, Pajak TF, Forastiere A, et al. Precisely dening highrisk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head Neck 1998;20:588594. 8. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:571578. 9. Rosenthal DI, Liu L, Lee JH, et al. Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck. Head Neck 2002; 24:115126. 10. Langendijk JA, de Jong MA, Leemans CR, et al. Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time. Int J Radiat Oncol Biol Phys 2003;57:693700. 11. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. Risk-group denition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Cancer 2005;104:14081417. 12. Jonkman A, Kaanders JH, Terhaard CH, et al. Multicenter validation of recursive partitioning analysis classication for patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:119125. 13. Leon X, Lopez M, Pineiro Z, Langendijk JA, Leemans CR, Quer M. External validation of a risk group dened by recursive partitioning analysis in patients with head and neck carcinoma treated with surgery and postoperative radiotherapy. Head Neck 2007;29:815821. 14. Shaw RJ, Lowe D, Woolgar JA, et al. Extracapsular spread in oral squamous cell carcinoma. Head Neck 2010;32:714722. 15. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: rst report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1992;26:311. 16. Snow GB, Annyas AA, van Slooten EA, Bartelink H, Hart AAM. Prognostic factors of neck node metastasis. Clin Otolaryngol 1982;7:185192. 17. DeSanto LW, Beahrs OH, Holt JJ, OFallon WM. Neck dissection and combined therapy. Study of effectiveness. Arch Otolaryngol 1985;111:366370. 18. OBrien CJ, Soong SJ, Urist MM, Maddox AW. Is modied radical neck dissection only a staging procedure? Cancer 1987;59:994999.

What risk is low enough to allow for safe avoidance of PORT to the neck? At the moment it is unclear where to draw a decision line. The only well-characterized indication for adjuvant irradiation of the dissected neck is ECE, for which the PORT should be supplemented with concomitantly applied chemotherapy. The number of nodes involved with cancer that requires a combined approach has yet to be determined. In accord with the available evidence, the most pressing questions for scientic evaluation would be whether PORT is indicated in cases of multiple nodes or pN1 disease. Particularly in view of more recent reports, specically questioning the value of PORT in the pN1 setting and in the absence of ECE,38,39 PORT seems to be of benet for disease control in the neck when a single node of <3 cm with no ECE has been found to be positive. Similarly, extensive analyses of the SEER database have revealed that implementation of PORT in the pN1 setting could have a survival advantage.4042 However, because these studies suffer from all of the limitations inherent in retrospective analyses, including diversity in primary tumor types, disease stages, and treatment procedures performed, prospective appraisal of this question is essential. According to Moergel et al,56 who recently presented a design for a prospective multicenter randomized control clinical trial, this question will soon be properly addressed. Under well-described guidelines for surgical procedures and subsequent PORT, patients with early-stage (pT12) oropharyngeal and oor of mouth SCC with a singular ipsilateral lymph node metastasis (pN1) without ECE will be randomized after radical surgery to one of the 2 treatment arms (ie, PORT/no PORT). The primary endpoint in this study will be overall survival with a strong emphasis on quality-of-life issues evaluated in the context of secondary

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19. Medina JE, Byers RM. Supraomohyoid neck dissection: rationale, indication, and surgical technique. Head Neck 1989;11:111122. 20. Traynor SJ, Cohen JI, Gray J, Andersen PE, Everts EC. Selective neck dissection and the management of the node-positive neck. Am J Surg 1996;172:654657. 21. Barzan L, Talamini R. Analysis of prognostic factors for recurrence after neck dissection. Arch Otolaryngol Head Neck Surg 1996;122:12991302. 22. Wolfensberger M, Zbaeren P, Dulguerov P, Muller W, Arnoux A, Schmid S. Surgical treatment of early oral carcinoma: results of a prospective controlled multicenter study. Head Neck 2001;22: 525530. 23. Coster JR, Foote RL, Olsen KD, Jack SM, Schaid DJ, DeSanto LW. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys 1992;23:743749. 24. Iganej S, Kagan R, Anderson P, et al. Metastatic squamous cell carcinoma of the neck from an unknown primary: management options and patterns of relapse. Head Neck 2002;24:236246. 25. Patel RS, Clark J, Wyten R, Gao K, OBrien CJ. Squamous cell carcinoma from an unknown head and neck primary site: a selective treatment approach. Arch Otolaryngol Head Neck Surg 2007;133:12821287. 26. Gourin CG, Conger BT, Porubsyky ES, Sheils WC, Bilodeau PA, Coleman TA. The effect of occult nodal metastases on survival and regional control in patients with head and neck squamous cell carcinoma. Laryngoscope 2008;118:11911194. 27. Hosal AS, Carrau RL, Johnson JT, Myers EN. Selective neck dissection in the management of the clinically node-negative neck. Laryngoscope 2000;110:20372040. 28. Chepeha DB, Hoff PT, Taylor RJ, Bradford CR, Teknos TN, Esclamado RM. Selective neck dissection for the treatment of neck metastasis from squamous cell carcinoma of the head and neck. Laryngoscope 2002;112:434438. 29. Schmitz S, Machiels JP, Weynand B, Gregoire V, Hamoir M. Results of selective neck dissection in the primary management of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2009;266:437443. 30. Olsen KD, Caruso M, Foote RL, et al. Histopathologic predictors of recurrence after neck dissection in patients with lymph node involvement. Arch Otolaryngol Head Neck Surg 1994;120:1370 1374. 31. Leemans CR, Tiwari R, van der Waal I, Karim ABMF, Nauta JJP, Snow GB. The efcacy of comprehensive neck dissection with or without postoperative radiotherapy in nodal metastases of squamous cell carcinoma of the upper respiratory and digestive tract. Laryngoscope 1990;100:11941198. 32. Spiro RH, Morgan GJ, Strong EW, Shah JP. Supraomohyoid neck dissection. Am J Surg 1996;172:650653. 33. Byers RM, Clayman GL, McGill D, et al. Selective neck dissections for squamous cell carcinoma of the upper aerodigestive tract: patterns of regional failure. Head Neck 1999;21:499505. 34. Brazilian Head and Neck Cancer Study Group. Results of prospective trial on elective modied radical classical versus supraomohyoid neck dissection in the management of oral squamous cell carcinoma. Am J Surg 1998;176:422427. 35. Kolli VR, Datta RV, Orner JB, Hicks WL, Loree TR. The role of supraomohyoid neck dissection in patients with positive nodes. Arch Otolaryngol Head Neck Surg 2000;126:413416. 36. Schiff BA, Roberts DB, El-Naggar A, Garden AS, Myers JN. Selective vs modied neck dissection and postoperative radiotherapy vs observation in the treatment of squamous cell carcinoma of the oral tongue. Arch Otolaryngol Head Neck Surg 2005;131:874878. 37. Ambrosch P, Kron M, Pradier O, Steiner W. Efcacy of selective neck dissection: a review of 503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper

38. 39. 40.

41.

42.

43. 44. 45. 46. 47.

48. 49. 50.

51.

52. 53. 54. 55.

56.

aerodigestive tract. Otolaryngol Head Neck Surg 2001;124:180 187. Jackel MC, Ambrosch P, Christiansen H, Martin A, Steiner W. Value of postoperative radiotherapy in patients with pathologic N1 neck disease. Head Neck 2008;30:875882. Chen TC, Wang CT, Ko JY, et al. Postoperative radiotherapy for primary early oral tongue cancer with pathologic N1 neck. Head Neck 2010;32:555561. Lavaf A, Genden EM, Cesaretti JA, Packer S, Kao J. Adjuvant radiotherapy improves overall survival for patients with lymph node-positive head and neck squamous cell carcinoma. Cancer 2008;12:535543. Kao J, Lavaf A, Teng MS, Huang D, Genden EM. Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage. Int J Radiat Oncol Biol Phys 2008;71:362370. Shrime MG, Gullane PJ, Dawson L, et al. The impact of adjuvant radiotherapy on survival in T12N1 squamous cell carcinoma of the oral cavity. Arch Otolaryngol Head Neck Surg 2010;136:225228. Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head neck Surg 1994;120:699702. Pitman KT. Rationale for elective neck dissection. Am J Otolaryngol 2000;21:3137. Pillsbury HC III, Clark M. A rationale for therapy of the N0 neck. Laryngoscope 1997;107:12941315. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tract. Cancer 1972;29:14461449. Medina JE. Management of the neck in squamous cell carcinoma of the head and neck. In: Ensley JF, Gutkinf JS, Jacobs JR, Lippman SM, editors. Head and neck cancer. Amsterdam: Academic Press; 2003. pp 317327. Withers HR, Peters LJ, Taylor JMG. Doseresponse relationship for radiation therapy of subclinical disease. Int J Radiat Oncol Biol Phys 1995;31:353359. Ferlito A, Rinaldo A, Silver CE, et al. Elective and therapeutic selective neck dissection. Oral Oncol 2006;42:1425. Vergeer MR, Doornaert PA, Jonkman A, et al. Ipsilateral irradiation for oral and oropharyngeal carcinoma treated with primary surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 2010 Feb 24. [Epub ahead of print]. Brazilian Head and Neck Cancer Study Group. End results of a prospective trial on elective lateral neck dissection vs. type III modied radical neck dissection in the management of supraglottic and transglottic carcinomas. Head Neck 1999;21:694702. Candela FC, Kothar K, Shah JP. Patterns of cervical node metastases from squamous cell carcinoma of the oropharynx and hypopharynx. Head Neck 1990;12:197203. Davidson BJ, Kulkarny V, Delacure MD, Shah JP. Posterior triangle metastases of squamous cell carcinoma of the upper aerodigestive tract. Am J Surg 1993;166:395398. Shah JP. Pattern of cervical lymph node metastases form squamous carcinoma of the upper aerodigestive tract. Am J Surg 1990;160:405409. Byers RM, Weber RS, Andrews T, McGill D, Kare R, Wolf P. Frequency and therapeutic implications of skip metastases in the neck from squamous cell carcinoma of the oral tongue. Head Neck 1997;19:1419. Moergel M, Jahn-Eimermacher A, Krummenauer F, et al. Effectiveness of adjuvant radiotherapy in patients with oropharyngeal and oor of the mouth squamous cell carcinoma and concomitant histologic verication of singular ipsilateral cervical lymph node metastasis (pN1-state): a prospective multicenter randomized controlled clinical trial using a comprehensive cohort design. Trials 2009;10:118 (abstract).

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