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Efficacy of super-selective neck dissection following chemoradiation for advanced head and neck cancer
Oral Oncology 48 (2012) 1185–1189
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Efficacy of super-selective neck dissection following chemoradiation for advanced head and neck cancer K. Thomas Robbins a,b,⇑, Muthuswamy Dhiwakar a,b, Francisco Vieira d, Krishna Rao a,c, James Malone a,b a
Simmons Cancer Institute at SIU, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States Division of Otolaryngology – Head & Neck Surgery, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States c Division of Medical Oncology, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States d Department of Otolaryngology – Head & Neck Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, United States b
a r t i c l e
i n f o
Article history: Received 6 February 2012 Received in revised form 30 April 2012 Accepted 28 May 2012 Available online 15 July 2012 Keywords: Super-selective neck dissection Head and neck cancer Chemoradiation
s u m m a r y Background: Hypothesizing that neck-level specific locations of residual lymph node metastases following chemoradiation for head and neck cancer are highly predictable, the efficacy of the more targeted lymphadenectomy procedure called super-selective neck dissection (SSND) was evaluated. Methods: A retrospective analysis of the databases from 2 institutions indicated that 35 SSND’s were performed on 30 patients following chemoradiation as either a planned or early salvage intervention. Results: Over a median follow-up of 33 (range: 8–72) months, 8 patients developed recurrent disease (3 primary, 5 distant) but there were no isolated recurrences in the neck. The projected 5 year disease specific survival rate for the group was 60%. Conclusions: SSND is an effective intervention for patients with advanced head and neck cancer treated with chemoradiation whose risk for residual nodal disease is confined to one level. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Chemoradiation has become a common treatment approach for patients with advanced head and neck cancer. Meta-analyses have demonstrated a significant survival advantage for this combined modality approach compared to radiation alone.1,2 Furthermore, chemoradiation offers the hope for preservation of organ function compared to historical treatments that involve radical extirpative surgery.3,4 Despite the progress demonstrated with chemoradiation, there remains an ongoing uncertainty as to the best management of neck metastases associated with head and neck cancer. Initially, the common approach was to perform a neck dissection on all patients who presented with bulky nodal disease regardless of the response to the initial chemoradiation, the so called planned neck dissection.5–11 However, when reports emerged indicating a high rate of regional disease control when neck dissection was not performed among patients who had a clinical complete response to chemoradiation, the use of planned neck dissection came into question.13,14 Thus, there is an emerging trend to perform neck dissection only for patients who did not achieve a clinical complete ⇑ Corresponding author at: Simmons Cancer Institute at SIU, PO Box 19677, 315 West Carpenter St., Springfield, IL 62794-9677, United States. Tel.: +1 217 545 6818; fax: +1 217 545 0057. E-mail address: [email protected] (K.T. Robbins). 1368-8375/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2012.05.025
response in the neck, which is referred to as salvage neck dissection.15–18 Despite the paradigm shift from planned neck dissection to salvage neck dissection, there remain additional controversies in the management of the post-chemoradiation neck. One of these is determining which lesions represent actual residual viable cancer versus non-viable cancer or fibrosis. Although functional imaging technology may eventually help resolve this problem, current methods using PET are considered to be inaccurate in the early phase of follow-up.19,20 However, our own experience is that PET-CT has a high negative predictive value when performed at 8 weeks post-chemoradiation.21 Another controversy relates to the type of the neck dissection. While the traditional philosophy was to remove lymph node groups in all five neck levels,5 more recent reports have demonstrated efficacy of selective neck dissection.6,12,22–25 Advocates of selective neck dissection rely on the concept that the pattern of nodal metastases in the cervical region is predictable and that neck levels that were uninvolved prior to treatment are very unlikely to harbor residual disease following chemoradiation. With the growing acceptance of the selective neck dissection for controlling metastases following chemoradiation, there arises an additional question that addresses the option of performing a more targeted neck dissection, namely one that removes only the neck levels at greatest risk for harboring clinically positive disease. For example, in most patients treated with chemoradiation,
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the residual nodal disease is limited clinically to a single neck level, usually level II.26 Would it be feasible and safe to remove only the clinical disease in the single neck level and its adjacent level? We have tested this hypothesis previously by analyzing a series of neck dissection specimens and correlating presence of pathologic positive residual neck level specific nodal disease with corresponding pre- and post-chemoradiation imaging studies.26 The correlations supported the hypothesis that targeted neck dissection, which we referred to as super-selective neck dissection (SSND), is feasible among patients whose residual neck node disease is confined to a single level. In addition to our anatomical pathologic study, we have shown in another analysis of clinical outcomes following neck dissection after chemoradiation, namely RADPLAT, that there were no regional recurrences noted among a small subset (7 patients) in which a SSND was performed.22 In this current study, we now report the treatment outcomes of a larger series of 35 super-selective neck dissections to further address the hypothesis that this procedure is effective in controlling advanced nodal disease in patients with head and neck cancer following treatment with chemoradiation. Patients and methods The data analyzed in this study was obtained from two institutions at which the senior author worked. The database at the University of Tennessee, Memphis was collected prospectively for all patients with head and neck cancer undergoing the chemoradiation protocol known as RADPLAT between 1993 and 1999. A retrospective analysis of this database was done for all of the patients who had a neck dissection performed. At Southern Illinois University, the data was collected retrospectively on all patients with head and neck cancer treated with chemoradiation who subsequently had a neck dissection. The patients in the second subset were treated between 2004 and 2009, during which time a variety of chemoradiation protocols were used. The data sets were combined to analyze the treatment outcomes for those patients who had a SSND performed. Institutional review board approvals were obtained from each institution before the data was collected. Only patients with newly diagnosed, biopsy-proven mucosal SCCHN and eligible for curative treatment were included. Excluded were those with a previous head and neck cancer, prior surgery in the targeted neck, previous treatment for the index cancer (surgery, chemotherapy, radiation or biological therapy) or distant metastasis. At both centers, the treatment plan was agreed upon in a multidisciplinary oncology forum. As stated, the chemoradiation protocols used varied during the time span that patients were treated. The most common one was RADPLAT,27 which consisted of 4 weekly infusions of intra-arterial cisplatin (150 mg/m2) and intravenous sodium thiosulphate neutralization and concomitant radiation. Other protocols included concurrent chemoradiation with intravenous carboplatin (AUC 1.5 mg/m2) weekly or cisplatin (100 mg/m2) every 3 weeks, or induction chemotherapy with docetaxel (175 mg/m2, day 1), cisplatin (100 mg/m2, day 2) and 5-fluorouracil (500–750 mg/m2, days 2–6) for a total of 3 cycles each 3 weeks apart, followed by concurrent chemoradiation. An additional patient was enrolled into the ECOG 2303 protocol: Phase II multi-center trial evaluating weekly induction with cetuximab (250 mg/m2), paclitaxel (90 mg/ m2) and carboplatin (AUC of 2) for 6 weeks, followed by the same combination weekly (paclitaxel 30 mg/m2, carboplatin AUC of 1 and cetuximab 250 mg/m2) from week 9 to 13, along with concurrent radiation from week 9 to 13. Overall, radiotherapy was delivered at 1.8–2 Gy/day, 5 days/ week over 6–7 weeks, to a cumulative median dose of 70 (range: 68.4–74.8) Gy for the primary and clinically overt nodal levels,
and to a median dose of 52 (range 50–54) Gy for the clinically negative nodal levels. Both sides of the neck were irradiated in all patients, irrespective of the lymph node status. All patients underwent computed tomography (CT) with or without positron emission tomography (PET) before treatment and at 6–8 weeks following completion of chemoradiation. The post-treatment scans were reviewed in conjunction with the head and neck radiologist for each institution. Presence or absence of residual disease at the primary site and regional lymph nodes was noted. If disease was felt to be present in the neck, the involved levels and sublevels, size of lymph nodes and any extranodal soft tissue effacement were specifically recorded. For all patients in the analysis, the SSND was performed following chemoradiation as either a planned or early salvage intervention. For patients treated 1993–1995, most SSNDs were performed as a planned intervention in patients with bulky (N2 or N3) nodal disease, regardless of the extent of the regional response to chemoradiation. For the remaining patients, SSNDs were done only for patients with less than a complete response in the neck. SSND was defined as the compartmental removal of one or two neck levels and encompassing all boundaries of each targeted neck level. The selection of the neck levels to be dissected was based on the location of the primary tumor, clinical evidence of disease by neck level prior to treatment, and the presence of clinical neck level specific residual disease post-chemoradiation. As a precaution, during the operative procedure, if there was any palpable abnormality involving a neck level that had not been predicted by the pre-surgical evaluation, this level was included as part of the dissection. The surgical specimens were routinely separated by the surgeon and submitted to the pathologist in separate containers corresponding to each neck level and each relevant sublevel. Residual tumor was considered present if intact malignant cells were identified in the specimen. The presence of keratin debris, necrotic cells, granulomas, sclerotic or hyalinized lymph nodes, extensive fibrosis or histiocytic reaction, without associated malignant cells were considered negative for residual carcinoma. Data was analyzed according to the clinical staging, pathological findings of the neck specimen, and treatment outcomes. The complete and partial neck responders were compared with regard to various demographic, tumor and treatment characteristics. Chi-Square test with Yates correction, Mann–Whitney U test, t-test or Analysis of Variance (ANOVA) as appropriate was used to test for any difference, with p < 0.05 considered statistically significant. For disease failure, the sites of recurrence were designated as follows: local if recurrence was identified at the primary site (with or without regional or distant disease); regional if recurrence involved the neck without associated disease at the primary site and with or without distant metastases; and distant if there was evidence of distant metastasis without disease at the primary or regional site. Kaplan–Meier survival plots were constructed to determine the projected 5-year diseasespecific survival. The major endpoint that best represented the therapeutic effect of the super-selective neck dissection was considered to be regional failure. A review of the literature identified 24 publications of patients with head and neck cancer who were treated with chemoradiation and in whom the regional failure rate was reported. Among them, the average recurrence rate was 12% (range 0–35%). Based on this, we calculated the probability of failure in the neck to be 1% using the binomial distribution, which is ideally suited for small sample sizes. The probability of a regional recurrence would, in fact, have to drop to 8% in order to have at least a 5% chance of obtaining 0 out of 35 surgeries regional recurrences.
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Results There were 35 SSNDs performed involving 30 patients treated with chemoradiation for advanced head and neck cancer. The details of the patient demographics and tumor characteristics are outlined in Table 1. Most patients completed the fully intended treatment. However, 3 patients in complete response group received between 47 and 50 Gy of radiation. One patient in the partial response group received a total dose of 50 Gy. Curtailed radiation therapy was mainly due to treatment-related toxicity. There were 23 SSNDs performed in patients who had a complete response in the neck following chemoradiation and thus categorized as a planned neck dissection. Among this subset, there were 3 patients who also underwent resection of the mucosal lesion at the time of the SSND because of an incomplete response in the primary site. There were 12 SSNDs performed in patients who did not have a complete response following chemoradiation and thus categorized as salvage neck dissection procedures. In this latter group, all patients achieved a CR at the primary site. The median time interval between completion of chemoradiation and the neck surgery for the complete responders was 9 (range: 4–30) weeks and for the partial responders was 10 (range: 6–16) weeks.
There were 8 neck specimens in which there was residual cancer found on pathologic examination. This involved 1 specimen in the complete response group (4%) and 7 specimens in the partial response group (67%). The specific levels with residual nodal disease are shown in Table 1. Only one of the pathological positive nodal metastases exhibited extracapsular extension. There were no major complications attributable to SSND and there were no instances of postoperative mortality. Over a median follow-up of 33 (range: 8–72) months, there was a total of 8 recurrences, all of which occurred at either the primary site or at distant sites. There were no isolated recurrences in the neck, although there was one patient who was diagnosed to have a recurrence in the primary site and neck simultaneously (Fig. 1). The projected 5 year disease specific survival rate for the group was 60%.
Discussion The concept of removing only 2 neck levels in neck dissection is not new, particularly when used as a component of primary surgery. For example, Ambrosh et al. performed neck dissection limited to levels II and III on the majority of patients with laryngeal cancer and clinically negative neck disease undergoing transoral
Table 1 Distribution of patient demographics, disease site and stage, treatment protocol, and neck levels dissected by total group and clinical response. Entire group (30 patients [35 heminecks]) Age 55.3 (30–78) Sex 24:6 Race (white:black) 23:7 Primary site Oral cavity 3 Oropharynx 21 Larynx 3 Hypopharynx 2 Occult 1 cT classification before chemoradiation Tx 1 T1 2 T2 1 T3 15 T4 11 cN classification of targeted neck before chemoradiation N1 9 N2a 9 N2b 15 N3 2 Chemo protocol RADPLAT 25 RTOG 9615 1 Concurrent chemoxRT 2 ECOG 2303 1 Induct followed by concxRT 1 Neck levels dissected in targeted neck II, III 28 I (A,B) 1 I, II 1 II 4 III, IV 1 Contralateral neck SuperSND 5 SND 0 MRND/RND 0 Recurrence Primary 3 Ipsilateral regional 0 Contralateral regional 0 Distant 5 Second H and N primary 2 NS: Not Significant.
Complete responders in the neck
Partial responders in the neck
Difference (p value)
55.1 (30–78) 16:3 12:7
59.3 (36–78) 8:3 11:0
NS NS 0.029 NS
2 15 1 1 0
1 6 2 1 1
0 0 1 9 9
1 2 0 6 2
5 6 10 2
4 3 5 0
18 1 0 0 0
7 0 2 1 1
17 1 1 4 –
11 – – – 1
4 0 0
1 0 0
2 0 0 4 0
1 0 0 1 2
NS
NS
NS
NS
NS
NS
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Figure 1 Kaplan–Meier plots for neck control and DSS.
laser resection.28 However, when applied as part of the primary treatment, post-operative adjuvant radiation therapy is usually recommended for patients found to have occult nodal disease. The data in this analysis suggest that the use of SSND is an effective treatment strategy applicable to a specific subset of patients following chemoradiation for advanced head and neck cancer. With this latter application, it may be viewed as an adjuvant therapy rather than part of the primary treatment. It is based on the principle that neck levels with clinically absent metastases prior to treatment, which then receive a therapeutic dose of radiation along with concurrent chemotherapy, should have a very low risk for having occult residual metastases following treatment. This should obviate the need to surgically remove the nodes from these levels, even though other neck levels had clinically positive disease. This rationale has also served as the basis for performing the more standard selective neck dissection instead of comprehensive neck dissection following chemoradiation. However, limiting the dissection to 2 or less levels represents a further modification and careful consideration. In terms of the specific type of chemoradiation protocol received, the study subjects could be viewed as heterogenous. However, the criteria for entry into the analysis were the presence of, or risk for persistent disease regardless of the specific characteristics of the chemoradiation protocol. At the point of intervention for the SSND, whether planned or for salvage, the subjects could be viewed as two homogeneous groups with regard to disease status. Whether the neck dissection was done as a planned intervention or for salvage, the primary aim was not to test the efficacy of the chemoradiation protocol itself. There were 3 patients in the study who did not achieve a complete response in the primary site and underwent surgical salvage of the persistent mucosal disease concurrent with the SSND. While the inclusion of such patients may potentially bias the results toward diminishing the efficacy of SSND, the absence of disease recurrence in the neck following SSND would appear to negate this possible negative influence. Others have alluded to the concept of SSND and supported it as well. Goguen et al. reported the use of CT imaging as a method to identify patients with neck level specific metastases. They reported likelihood rates of 94% that SSND would have been a suitable procedure to remove the positive nodal disease.29
Strictly speaking, the procedure of removing 2 or less neck levels to eradicate lymph node disease fits the criteria established by the AAO-HNS for selective neck dissection (Academy reference). In other words, any neck dissection procedure that spares one or more neck levels removed in the radical neck dissection is a selective neck dissection. Therefore, one must consider the SSND as a sub-type of SND based on the original definition. The procedure of SSND itself has the advantage over more extensive neck dissections, including the SND, because the surgical field is limited to only 2 levels and the incision can be kept to a short length, usually around 8 cm. For patients who require bilateral neck dissections, two separate neck incisions can be made and it is not necessary to connect the two surgical fields. The end result following SSND is that there is a limited surgical field, which reduces the likelihood of developing extensive fibrosis of the soft tissue of the neck. The recovery from the surgery is rapid, and there is less risk to surrounding vital structures. All of these advantages become even more important in considering the long course of treatment with chemotherapy and radiation over many weeks that most patients are required to undergo. A shortcoming of this analysis is that assessment using specific measures of dysfunction related to the surgical intervention was not routinely documented in the medical records. For a larger group of patients treated with chemoradiation who then had a neck dissection including more extensive types, it has been reported that wound healing complications are relatively uncommon.30 In this particular analysis, none of the patients had any major acute wound healing problems and there were no instances reported of chronic complications such as severe fibrosis with restriction of neck movements. However, specific data related to neck function is difficult to determine in a retrospective analysis and requires a prospective study for specific documentation. For patients in this study treated during the earlier years, SSND was performed as a planned procedure. There is now a growing body of evidence that planned neck dissection is not necessary even for patients who have extensive neck disease, provided there is an unequivocal complete response to the chemoradiation. Opponents to this philosophy argue that a substantial proportion of patients who undergo neck dissection following a complete response to chemoradiation who have pathological evidence of persistent disease. However, in large series of patients who are followed
K.T. Robbins et al. / Oral Oncology 48 (2012) 1185–1189
without neck dissection, very few have a regional recurrence.15 The apparent contradiction can be explained by the fact that most patients do not have residual cancer that is viable. Thus, the indications for SSND have been reduced based on this philosophy. The results of this analysis indicate that SSND is an effective intervention regardless of whether this was performed as a planned procedure or for salvage. In the subset of patients treated in the early part of the study when it was considered prudent to dissect the neck for all patients with N2–3 disease regardless of response to the chemoradiation, there were no recurrences in the neck. Similarly, when neck dissection was done only for patients with less than a complete response, none of the patients in this subset whose residual nodal disease was confined to a single neck level had a recurrence in the neck following a SSND. For both patient subsets, the application of the more targeted procedure proved to be highly effective. The fact that SSND is a limited procedure and well tolerated, makes this intervention an attractive option to recommend to patients who have completed chemoradiation and who continue to have clinical evidence of persistent nodal disease confined to a single neck level. Oftentimes there is near resolution of the nodes and the PET/CT indicates decreased but not absent uptake. While the option of continued observation is useful for some patients, in others there is a need to intervene sooner. Under this circumstance, the SSND approach is very practical and definitive. We conclude that for patients with advanced head and neck cancer treated with chemoradiation whose residual nodal disease is confined to one level, SSND is an effective intervention to minimize the risk of disease recurrence in the regional nodes. Also, one intuitively would expect lesser surgical morbidity related to the more limited and targeted procedure of SSND compared to more extensive neck dissections. However, prospective studies are needed to quantify this perceived advantage. Conflict of interest statement None declared. References 1. Bourhis J, Amand C, Pignon JP, MACH-NC Collaborative Group. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemotherapy. J Clin Oncol 2004;22(Suppl.):489s. 2. Blanchard P, Baujat B, Holostenco V, On behalf of the MACH-CH Collaborative group, et al. Meta-analysis of chemotherapy in head and neck cancer (MACHNC): a comprehensive analysis by tumour site. Radiother Oncol 2011. June 16. 3. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J Med 1991;324(24):1685–90. 4. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New Engl J Med 2003;349(22):2091–8. 5. Lavertu P, Adelstein DJ, Saxton JP, et al. Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer. Head Neck 1997;19:559–66. 6. Stenson KM, Haraf DJ, Pelzer H, et al. The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection. Arch Otolaryngol Head Neck Surg 2000;126:950–6. 7. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;58(5):1418.
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8. Gupta T, Agarwal JP. Planned neck dissection following chemo-radiotherapy in advanced HNSCC. Int Semin Surg Oncol 2004;1(1):6. 9. Sewall GK, Palazzi-Churas KL, Richards GM, Hartig GK, Harari PM. Planned postradiotherapy neck dissection: rationale and clinical outcomes. Laryngoscope 2007;117(1):121–8. 10. Hitchcock YJ, Bentz BG, Sharma PK, et al. Planned neck dissection after definitive radiotherapy or chemoradiation for base of tongue cancers. Otolaryngol Head Neck Surg 2007;137(3):422–7. 11. Sabatini PR, Ducic Y. Planned neck dissection following primary chemoradiation for advanced-stage head and neck cancer. Otolaryngol Head Neck Surg 2009;141(4):474–7. 12. Robbins KT, Wong FS, Kumar P, et al. Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 1999;125(6):670–5. 13. 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(2): 135–9. 14. Ferlito A, Corry J, Silver CE, Shaha AR, Thomas Robbins K, Rinaldo A. Planned neck dissection for patients with complete response to chemoradiotherapy: a concept approaching obsolescence. Head Neck 2010;32(2):253–61 [review]. 15. Corry J, Peters L, Fisher R, et al. N2–N3 neck nodal control without planned neck dissection for clinical/radiologic complete responders-results of Trans Tasman Radiation Oncology Group Study 98.02. Head Neck 2008;30(6):737–42. 16. van der Putten L, van den Broek GB, de Bree R, et al. Effectiveness of salvage selective and modified radical neck dissection for regional pathologic lymphadenopathy after chemoradiation. Head Neck 2009;31(5):593–603. 17. Malone J, Robbins KT. Neck dissection after chemoradiation for carcinoma of the upper aerodigestive tract: indications and complications. Curr Opin Otolaryngol Head Neck Surg 2010;18(2):89–94 [review]. 18. Rengan R, Pfister DG, Lee NY, et al. Long-term neck control rates after complete response to chemoradiation in patients with advanced head and neck cancer. Am J Clin Oncol 2008;31:465–9. 19. Lyford-Pike S, Ha PK, Jacene HA, Saunders JR, Tufano RP. Limitations of PET/CT in determining need for neck dissection after primary chemoradiation for advanced head and neck squamous cell carcinoma. ORL J Otorhinolaryngol Relat Spec 2009;71(5):251–6 [Epub 2009 September 16]. 20. Gourin CG, Boyce BJ, Williams HT, Herdman AV, Bilodeau PA. Coleman TA Revisiting the role of positron-emission tomography/computed tomography in determining the need for planned neck dissection following chemoradiation for advanced head and neck cancer. Laryngoscope 2009;119(11):2150–5. 21. Malone JP, Gerberi MA, Vasireddy S, et al. Early prediction of response to chemoradiotherapy for head and neck cancer: reliability of restaging with combined positron emission tomography and computed tomography. Arch Otolaryngol Head Neck Surg 2009;135(11):1119–25. 22. Robbins KT, Doweck I, Samant S, Vieira F. Effectiveness of superselective and selective neck dissection for advanced nodal metastases after chemoradiation. Arch Otolaryngol Head Neck Surg 2005;131(11):965–9. 23. Cannady SB, Lee WT, Scharpf J, et al. Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma. Head Neck 2009;12 [Epub ahead of print]. 24. Mukhija V, Gupta S, Jacobson AS, et al. Selective neck dissection following adjuvant therapy for advanced head and neck cancer. Head Neck 2009;31:183–8. 25. Nouraei SAR, Upile T, Al-Yaghchi C, et al. Role of planned postchemoradiotherapy selective neck dissection in the multimodality management of head and neck cancer. Laryngoscope 2008;118:797–803. 26. Robbins KT, Shannon K, Vieira F. Superselective neck dissection after chemoradiation: feasibility based on clinical and pathologic comparisons. Arch Otolaryngol Head Neck Surg 2007;133(5):486–9. 27. Robbins KT, Kumar P, Harris J, et al. Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage iv head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of radiation therapy oncology group trial 9615. J Clin Oncol 2005;23(7):1447–54. 28. Ambrosch P, Kron M, Pradier O, Steiner W. Efficacy of selective neck dissection: a review of 503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper aerodigestive tract. Otolaryngol Head Neck Surg 2001;124(2):180–7. 29. Goguen LA, Chapuy CI, Sher DJ, et al. Utilizing computed tomography as a road map for designing selective and superselective neck dissection after chemoradiotherapy. Otolaryngol Head Neck Surg 2010;143(3):367–74. 30. Proctor E, Robbins KT, Vieira F, et al. Postoperative complications after chemoradiation for advanced head and neck cancer. Head Neck 2004;26: 272–7.
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Efficacy of super-selective neck dissection following chemoradiation for advanced head and neck cancer K. Thomas Robbins a,b,⇑, Muthuswamy Dhiwakar a,b, Francisco Vieira d, Krishna Rao a,c, James Malone a,b a
Simmons Cancer Institute at SIU, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States Division of Otolaryngology – Head & Neck Surgery, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States c Division of Medical Oncology, Southern Illinois University School of Medicine, Springfield, IL 62794-9677, United States d Department of Otolaryngology – Head & Neck Surgery, The University of Tennessee Health Science Center, Memphis, TN 38163, United States b
a r t i c l e
i n f o
Article history: Received 6 February 2012 Received in revised form 30 April 2012 Accepted 28 May 2012 Available online 15 July 2012 Keywords: Super-selective neck dissection Head and neck cancer Chemoradiation
s u m m a r y Background: Hypothesizing that neck-level specific locations of residual lymph node metastases following chemoradiation for head and neck cancer are highly predictable, the efficacy of the more targeted lymphadenectomy procedure called super-selective neck dissection (SSND) was evaluated. Methods: A retrospective analysis of the databases from 2 institutions indicated that 35 SSND’s were performed on 30 patients following chemoradiation as either a planned or early salvage intervention. Results: Over a median follow-up of 33 (range: 8–72) months, 8 patients developed recurrent disease (3 primary, 5 distant) but there were no isolated recurrences in the neck. The projected 5 year disease specific survival rate for the group was 60%. Conclusions: SSND is an effective intervention for patients with advanced head and neck cancer treated with chemoradiation whose risk for residual nodal disease is confined to one level. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Chemoradiation has become a common treatment approach for patients with advanced head and neck cancer. Meta-analyses have demonstrated a significant survival advantage for this combined modality approach compared to radiation alone.1,2 Furthermore, chemoradiation offers the hope for preservation of organ function compared to historical treatments that involve radical extirpative surgery.3,4 Despite the progress demonstrated with chemoradiation, there remains an ongoing uncertainty as to the best management of neck metastases associated with head and neck cancer. Initially, the common approach was to perform a neck dissection on all patients who presented with bulky nodal disease regardless of the response to the initial chemoradiation, the so called planned neck dissection.5–11 However, when reports emerged indicating a high rate of regional disease control when neck dissection was not performed among patients who had a clinical complete response to chemoradiation, the use of planned neck dissection came into question.13,14 Thus, there is an emerging trend to perform neck dissection only for patients who did not achieve a clinical complete ⇑ Corresponding author at: Simmons Cancer Institute at SIU, PO Box 19677, 315 West Carpenter St., Springfield, IL 62794-9677, United States. Tel.: +1 217 545 6818; fax: +1 217 545 0057. E-mail address: [email protected] (K.T. Robbins). 1368-8375/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2012.05.025
response in the neck, which is referred to as salvage neck dissection.15–18 Despite the paradigm shift from planned neck dissection to salvage neck dissection, there remain additional controversies in the management of the post-chemoradiation neck. One of these is determining which lesions represent actual residual viable cancer versus non-viable cancer or fibrosis. Although functional imaging technology may eventually help resolve this problem, current methods using PET are considered to be inaccurate in the early phase of follow-up.19,20 However, our own experience is that PET-CT has a high negative predictive value when performed at 8 weeks post-chemoradiation.21 Another controversy relates to the type of the neck dissection. While the traditional philosophy was to remove lymph node groups in all five neck levels,5 more recent reports have demonstrated efficacy of selective neck dissection.6,12,22–25 Advocates of selective neck dissection rely on the concept that the pattern of nodal metastases in the cervical region is predictable and that neck levels that were uninvolved prior to treatment are very unlikely to harbor residual disease following chemoradiation. With the growing acceptance of the selective neck dissection for controlling metastases following chemoradiation, there arises an additional question that addresses the option of performing a more targeted neck dissection, namely one that removes only the neck levels at greatest risk for harboring clinically positive disease. For example, in most patients treated with chemoradiation,
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the residual nodal disease is limited clinically to a single neck level, usually level II.26 Would it be feasible and safe to remove only the clinical disease in the single neck level and its adjacent level? We have tested this hypothesis previously by analyzing a series of neck dissection specimens and correlating presence of pathologic positive residual neck level specific nodal disease with corresponding pre- and post-chemoradiation imaging studies.26 The correlations supported the hypothesis that targeted neck dissection, which we referred to as super-selective neck dissection (SSND), is feasible among patients whose residual neck node disease is confined to a single level. In addition to our anatomical pathologic study, we have shown in another analysis of clinical outcomes following neck dissection after chemoradiation, namely RADPLAT, that there were no regional recurrences noted among a small subset (7 patients) in which a SSND was performed.22 In this current study, we now report the treatment outcomes of a larger series of 35 super-selective neck dissections to further address the hypothesis that this procedure is effective in controlling advanced nodal disease in patients with head and neck cancer following treatment with chemoradiation. Patients and methods The data analyzed in this study was obtained from two institutions at which the senior author worked. The database at the University of Tennessee, Memphis was collected prospectively for all patients with head and neck cancer undergoing the chemoradiation protocol known as RADPLAT between 1993 and 1999. A retrospective analysis of this database was done for all of the patients who had a neck dissection performed. At Southern Illinois University, the data was collected retrospectively on all patients with head and neck cancer treated with chemoradiation who subsequently had a neck dissection. The patients in the second subset were treated between 2004 and 2009, during which time a variety of chemoradiation protocols were used. The data sets were combined to analyze the treatment outcomes for those patients who had a SSND performed. Institutional review board approvals were obtained from each institution before the data was collected. Only patients with newly diagnosed, biopsy-proven mucosal SCCHN and eligible for curative treatment were included. Excluded were those with a previous head and neck cancer, prior surgery in the targeted neck, previous treatment for the index cancer (surgery, chemotherapy, radiation or biological therapy) or distant metastasis. At both centers, the treatment plan was agreed upon in a multidisciplinary oncology forum. As stated, the chemoradiation protocols used varied during the time span that patients were treated. The most common one was RADPLAT,27 which consisted of 4 weekly infusions of intra-arterial cisplatin (150 mg/m2) and intravenous sodium thiosulphate neutralization and concomitant radiation. Other protocols included concurrent chemoradiation with intravenous carboplatin (AUC 1.5 mg/m2) weekly or cisplatin (100 mg/m2) every 3 weeks, or induction chemotherapy with docetaxel (175 mg/m2, day 1), cisplatin (100 mg/m2, day 2) and 5-fluorouracil (500–750 mg/m2, days 2–6) for a total of 3 cycles each 3 weeks apart, followed by concurrent chemoradiation. An additional patient was enrolled into the ECOG 2303 protocol: Phase II multi-center trial evaluating weekly induction with cetuximab (250 mg/m2), paclitaxel (90 mg/ m2) and carboplatin (AUC of 2) for 6 weeks, followed by the same combination weekly (paclitaxel 30 mg/m2, carboplatin AUC of 1 and cetuximab 250 mg/m2) from week 9 to 13, along with concurrent radiation from week 9 to 13. Overall, radiotherapy was delivered at 1.8–2 Gy/day, 5 days/ week over 6–7 weeks, to a cumulative median dose of 70 (range: 68.4–74.8) Gy for the primary and clinically overt nodal levels,
and to a median dose of 52 (range 50–54) Gy for the clinically negative nodal levels. Both sides of the neck were irradiated in all patients, irrespective of the lymph node status. All patients underwent computed tomography (CT) with or without positron emission tomography (PET) before treatment and at 6–8 weeks following completion of chemoradiation. The post-treatment scans were reviewed in conjunction with the head and neck radiologist for each institution. Presence or absence of residual disease at the primary site and regional lymph nodes was noted. If disease was felt to be present in the neck, the involved levels and sublevels, size of lymph nodes and any extranodal soft tissue effacement were specifically recorded. For all patients in the analysis, the SSND was performed following chemoradiation as either a planned or early salvage intervention. For patients treated 1993–1995, most SSNDs were performed as a planned intervention in patients with bulky (N2 or N3) nodal disease, regardless of the extent of the regional response to chemoradiation. For the remaining patients, SSNDs were done only for patients with less than a complete response in the neck. SSND was defined as the compartmental removal of one or two neck levels and encompassing all boundaries of each targeted neck level. The selection of the neck levels to be dissected was based on the location of the primary tumor, clinical evidence of disease by neck level prior to treatment, and the presence of clinical neck level specific residual disease post-chemoradiation. As a precaution, during the operative procedure, if there was any palpable abnormality involving a neck level that had not been predicted by the pre-surgical evaluation, this level was included as part of the dissection. The surgical specimens were routinely separated by the surgeon and submitted to the pathologist in separate containers corresponding to each neck level and each relevant sublevel. Residual tumor was considered present if intact malignant cells were identified in the specimen. The presence of keratin debris, necrotic cells, granulomas, sclerotic or hyalinized lymph nodes, extensive fibrosis or histiocytic reaction, without associated malignant cells were considered negative for residual carcinoma. Data was analyzed according to the clinical staging, pathological findings of the neck specimen, and treatment outcomes. The complete and partial neck responders were compared with regard to various demographic, tumor and treatment characteristics. Chi-Square test with Yates correction, Mann–Whitney U test, t-test or Analysis of Variance (ANOVA) as appropriate was used to test for any difference, with p < 0.05 considered statistically significant. For disease failure, the sites of recurrence were designated as follows: local if recurrence was identified at the primary site (with or without regional or distant disease); regional if recurrence involved the neck without associated disease at the primary site and with or without distant metastases; and distant if there was evidence of distant metastasis without disease at the primary or regional site. Kaplan–Meier survival plots were constructed to determine the projected 5-year diseasespecific survival. The major endpoint that best represented the therapeutic effect of the super-selective neck dissection was considered to be regional failure. A review of the literature identified 24 publications of patients with head and neck cancer who were treated with chemoradiation and in whom the regional failure rate was reported. Among them, the average recurrence rate was 12% (range 0–35%). Based on this, we calculated the probability of failure in the neck to be 1% using the binomial distribution, which is ideally suited for small sample sizes. The probability of a regional recurrence would, in fact, have to drop to 8% in order to have at least a 5% chance of obtaining 0 out of 35 surgeries regional recurrences.
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Results There were 35 SSNDs performed involving 30 patients treated with chemoradiation for advanced head and neck cancer. The details of the patient demographics and tumor characteristics are outlined in Table 1. Most patients completed the fully intended treatment. However, 3 patients in complete response group received between 47 and 50 Gy of radiation. One patient in the partial response group received a total dose of 50 Gy. Curtailed radiation therapy was mainly due to treatment-related toxicity. There were 23 SSNDs performed in patients who had a complete response in the neck following chemoradiation and thus categorized as a planned neck dissection. Among this subset, there were 3 patients who also underwent resection of the mucosal lesion at the time of the SSND because of an incomplete response in the primary site. There were 12 SSNDs performed in patients who did not have a complete response following chemoradiation and thus categorized as salvage neck dissection procedures. In this latter group, all patients achieved a CR at the primary site. The median time interval between completion of chemoradiation and the neck surgery for the complete responders was 9 (range: 4–30) weeks and for the partial responders was 10 (range: 6–16) weeks.
There were 8 neck specimens in which there was residual cancer found on pathologic examination. This involved 1 specimen in the complete response group (4%) and 7 specimens in the partial response group (67%). The specific levels with residual nodal disease are shown in Table 1. Only one of the pathological positive nodal metastases exhibited extracapsular extension. There were no major complications attributable to SSND and there were no instances of postoperative mortality. Over a median follow-up of 33 (range: 8–72) months, there was a total of 8 recurrences, all of which occurred at either the primary site or at distant sites. There were no isolated recurrences in the neck, although there was one patient who was diagnosed to have a recurrence in the primary site and neck simultaneously (Fig. 1). The projected 5 year disease specific survival rate for the group was 60%.
Discussion The concept of removing only 2 neck levels in neck dissection is not new, particularly when used as a component of primary surgery. For example, Ambrosh et al. performed neck dissection limited to levels II and III on the majority of patients with laryngeal cancer and clinically negative neck disease undergoing transoral
Table 1 Distribution of patient demographics, disease site and stage, treatment protocol, and neck levels dissected by total group and clinical response. Entire group (30 patients [35 heminecks]) Age 55.3 (30–78) Sex 24:6 Race (white:black) 23:7 Primary site Oral cavity 3 Oropharynx 21 Larynx 3 Hypopharynx 2 Occult 1 cT classification before chemoradiation Tx 1 T1 2 T2 1 T3 15 T4 11 cN classification of targeted neck before chemoradiation N1 9 N2a 9 N2b 15 N3 2 Chemo protocol RADPLAT 25 RTOG 9615 1 Concurrent chemoxRT 2 ECOG 2303 1 Induct followed by concxRT 1 Neck levels dissected in targeted neck II, III 28 I (A,B) 1 I, II 1 II 4 III, IV 1 Contralateral neck SuperSND 5 SND 0 MRND/RND 0 Recurrence Primary 3 Ipsilateral regional 0 Contralateral regional 0 Distant 5 Second H and N primary 2 NS: Not Significant.
Complete responders in the neck
Partial responders in the neck
Difference (p value)
55.1 (30–78) 16:3 12:7
59.3 (36–78) 8:3 11:0
NS NS 0.029 NS
2 15 1 1 0
1 6 2 1 1
0 0 1 9 9
1 2 0 6 2
5 6 10 2
4 3 5 0
18 1 0 0 0
7 0 2 1 1
17 1 1 4 –
11 – – – 1
4 0 0
1 0 0
2 0 0 4 0
1 0 0 1 2
NS
NS
NS
NS
NS
NS
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Figure 1 Kaplan–Meier plots for neck control and DSS.
laser resection.28 However, when applied as part of the primary treatment, post-operative adjuvant radiation therapy is usually recommended for patients found to have occult nodal disease. The data in this analysis suggest that the use of SSND is an effective treatment strategy applicable to a specific subset of patients following chemoradiation for advanced head and neck cancer. With this latter application, it may be viewed as an adjuvant therapy rather than part of the primary treatment. It is based on the principle that neck levels with clinically absent metastases prior to treatment, which then receive a therapeutic dose of radiation along with concurrent chemotherapy, should have a very low risk for having occult residual metastases following treatment. This should obviate the need to surgically remove the nodes from these levels, even though other neck levels had clinically positive disease. This rationale has also served as the basis for performing the more standard selective neck dissection instead of comprehensive neck dissection following chemoradiation. However, limiting the dissection to 2 or less levels represents a further modification and careful consideration. In terms of the specific type of chemoradiation protocol received, the study subjects could be viewed as heterogenous. However, the criteria for entry into the analysis were the presence of, or risk for persistent disease regardless of the specific characteristics of the chemoradiation protocol. At the point of intervention for the SSND, whether planned or for salvage, the subjects could be viewed as two homogeneous groups with regard to disease status. Whether the neck dissection was done as a planned intervention or for salvage, the primary aim was not to test the efficacy of the chemoradiation protocol itself. There were 3 patients in the study who did not achieve a complete response in the primary site and underwent surgical salvage of the persistent mucosal disease concurrent with the SSND. While the inclusion of such patients may potentially bias the results toward diminishing the efficacy of SSND, the absence of disease recurrence in the neck following SSND would appear to negate this possible negative influence. Others have alluded to the concept of SSND and supported it as well. Goguen et al. reported the use of CT imaging as a method to identify patients with neck level specific metastases. They reported likelihood rates of 94% that SSND would have been a suitable procedure to remove the positive nodal disease.29
Strictly speaking, the procedure of removing 2 or less neck levels to eradicate lymph node disease fits the criteria established by the AAO-HNS for selective neck dissection (Academy reference). In other words, any neck dissection procedure that spares one or more neck levels removed in the radical neck dissection is a selective neck dissection. Therefore, one must consider the SSND as a sub-type of SND based on the original definition. The procedure of SSND itself has the advantage over more extensive neck dissections, including the SND, because the surgical field is limited to only 2 levels and the incision can be kept to a short length, usually around 8 cm. For patients who require bilateral neck dissections, two separate neck incisions can be made and it is not necessary to connect the two surgical fields. The end result following SSND is that there is a limited surgical field, which reduces the likelihood of developing extensive fibrosis of the soft tissue of the neck. The recovery from the surgery is rapid, and there is less risk to surrounding vital structures. All of these advantages become even more important in considering the long course of treatment with chemotherapy and radiation over many weeks that most patients are required to undergo. A shortcoming of this analysis is that assessment using specific measures of dysfunction related to the surgical intervention was not routinely documented in the medical records. For a larger group of patients treated with chemoradiation who then had a neck dissection including more extensive types, it has been reported that wound healing complications are relatively uncommon.30 In this particular analysis, none of the patients had any major acute wound healing problems and there were no instances reported of chronic complications such as severe fibrosis with restriction of neck movements. However, specific data related to neck function is difficult to determine in a retrospective analysis and requires a prospective study for specific documentation. For patients in this study treated during the earlier years, SSND was performed as a planned procedure. There is now a growing body of evidence that planned neck dissection is not necessary even for patients who have extensive neck disease, provided there is an unequivocal complete response to the chemoradiation. Opponents to this philosophy argue that a substantial proportion of patients who undergo neck dissection following a complete response to chemoradiation who have pathological evidence of persistent disease. However, in large series of patients who are followed
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without neck dissection, very few have a regional recurrence.15 The apparent contradiction can be explained by the fact that most patients do not have residual cancer that is viable. Thus, the indications for SSND have been reduced based on this philosophy. The results of this analysis indicate that SSND is an effective intervention regardless of whether this was performed as a planned procedure or for salvage. In the subset of patients treated in the early part of the study when it was considered prudent to dissect the neck for all patients with N2–3 disease regardless of response to the chemoradiation, there were no recurrences in the neck. Similarly, when neck dissection was done only for patients with less than a complete response, none of the patients in this subset whose residual nodal disease was confined to a single neck level had a recurrence in the neck following a SSND. For both patient subsets, the application of the more targeted procedure proved to be highly effective. The fact that SSND is a limited procedure and well tolerated, makes this intervention an attractive option to recommend to patients who have completed chemoradiation and who continue to have clinical evidence of persistent nodal disease confined to a single neck level. Oftentimes there is near resolution of the nodes and the PET/CT indicates decreased but not absent uptake. While the option of continued observation is useful for some patients, in others there is a need to intervene sooner. Under this circumstance, the SSND approach is very practical and definitive. We conclude that for patients with advanced head and neck cancer treated with chemoradiation whose residual nodal disease is confined to one level, SSND is an effective intervention to minimize the risk of disease recurrence in the regional nodes. Also, one intuitively would expect lesser surgical morbidity related to the more limited and targeted procedure of SSND compared to more extensive neck dissections. However, prospective studies are needed to quantify this perceived advantage. Conflict of interest statement None declared. References 1. Bourhis J, Amand C, Pignon JP, MACH-NC Collaborative Group. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemotherapy. J Clin Oncol 2004;22(Suppl.):489s. 2. Blanchard P, Baujat B, Holostenco V, On behalf of the MACH-CH Collaborative group, et al. Meta-analysis of chemotherapy in head and neck cancer (MACHNC): a comprehensive analysis by tumour site. Radiother Oncol 2011. June 16. 3. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J Med 1991;324(24):1685–90. 4. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New Engl J Med 2003;349(22):2091–8. 5. Lavertu P, Adelstein DJ, Saxton JP, et al. Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer. Head Neck 1997;19:559–66. 6. Stenson KM, Haraf DJ, Pelzer H, et al. The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection. Arch Otolaryngol Head Neck Surg 2000;126:950–6. 7. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;58(5):1418.
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