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A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Head and Neck Cancer
A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy Scott G. Soltys, M.D.,* Clara Y.H. Choi, M.D., Ph.D.,y Willard E. Fee, M.D.,z Harlan A. Pinto, M.D.,x,{ and Quynh-Thu Le, M.D.* Departments of *Radiation Oncology, yNeurosugery, zOtolaryngology, and xMedical Oncology, Stanford University Medical Center, Stanford; and {Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA Received Apr 26, 2011, and in revised form Jul 13, 2011. Accepted for publication Jul 29, 2011
Summary This study evaluated the role of a planned neck dissection (PND) in patients with N2-3 neck disease treated on prospective organ preservation protocols using chemoradiotherapy. Those with a neck cCR after chemoradiation were observed, all others received a PND. Patterns of failure suggest a PND would have benefited only 4% of those who achieved a neck cCR and cannot, therefore, be recommended. Nearly half of those with a clinical partial response had residual tumor in the neck dissection specimen and a PND should routinely follow.
Purpose: To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2eN3 nodal disease. Methods and Materials: We reviewed 90 patients with N2eN3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed. Results: The median follow-up durations for living and all patients were 8.3 years (range, 1.5e 16.3 year) and 5.4 years (range, 0.6e16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n Z 2); neck, primary, and distant (n Z 1); neck only (n Z 1); neck and distant (n Z 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n Z 1); neck and distant failure (n Z 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n Z 30) was 53%. The 5-year neck control rates after cCR, cPR/pCR, and cPR/pPR were 90%, 93%, and 78%, respectively (p Z 0.36). The 5-year disease-free survival rates for the cCR, cPR/pCR, and cPR/pPR groups were 53%, 75%, and 42%, respectively (p Z 0.04). Conclusion: In our series, patients with N2eN3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response. Ó 2012 Elsevier Inc. Keywords: Head-and-neck cancer, Chemoradiation, Neck dissection, Sequential
Reprint requests to: Scott G. Soltys, M.D., Stanford University Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847. Tel: (650) 724-1569; Fax: (650) 725-8231; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 83, No. 3, pp. 994e999, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.07.042
S. G. Soltys and C. Y. H. Choi contributed equally to this study. Conflict of interest: none.
Volume 83 Number 3 2012
Introduction Treatment with chemoradiotherapy for locally advanced headand-neck cancer results in similar survival rates as surgery plus adjuvant radiation (RT) (1e3) and allows for organ preservation. The optimal management of N2 and N3 neck disease after chemoradiotherapy is controversial. The American Society of Clinical Oncology practice guideline for larynx preservation recommends surgical treatment of the neck for patients with N2 or N3 disease, regardless of response (4). This is supported by some literature demonstrating locoregional control and survival benefits with the addition of planned neck dissection (PND) (5e8). Even in the setting of a clinical complete response (cCR) after chemoradiation, PND has been shown to improve disease-free survival (DFS) and overall survival (OS) compared with observation in some series (8). Alternatively, considering the potential morbidity of a PND and that it will only benefit those with an isolated neck failure, some have questioned the value of routine PND (9e11). Based on the low rates of isolated neck recurrence after a cCR to chemoradiation, some investigators recommend observation for patients achieving a cCR (12). Similarly, the National Comprehensive Cancer Network guidelines v2.2011 recommend observation for an imaging negative neck. The purpose of this study was to evaluate the role of PND in head-and-neck squamous cell carcinoma (SCCA) patients with N2 and N3 neck disease treated with sequential chemoradiotherapy (defined as induction chemotherapy followed by concurrent chemoradiotherapy). We retrospectively reviewed the outcomes in patients treated on two prospective sequential chemoradiotherapy organ preservation protocols to assess whether PND can be omitted in such patients.
Methods and Materials Patients The records of 90 head and neck SCCA patients with N2 and N3 neck disease treated at Stanford University Medical Center between 1991 and 2001 on two prospective organ preservation sequential chemoradiotherapy protocols (OSP2 (Organ Sparing Protocol 2) and OSP3) (13) were reviewed. Patient characteristics are shown in Table 1. Patients with nasopharynx and paranasal sinus primaries were excluded. Patients with unknown primary cancers with metastases to cervical lymph nodes were eligible because the primary endpoint of the study was the nodal response rate. Before treatment, all patients underwent a complete history and physical examination, laboratory studies (complete blood count, comprehensive chemistry panel, and 24-hour creatinine clearance), imaging studies (magnetic resonance imaging [MRI] or computed tomography [CT] of the head and neck sites, chest xray), and baseline audiograms.
Planned neck dissection after sequential chemoradiotherapy Table
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Patient characteristics
Age (y) Median (range) Sex M F Primary site Oral cavity* Oropharynx Larynx Hypopharynx* Unknown primary T stage T0 T1 T2 T3 T4 N stage N2a N2b N2c N3
58 (39e80) 76 (84) 14 (16) 3 60 8 18 2
(3) (67) (9) (20) (2)
2 10 28 14 37
(2) (11) (31)* (15) (41)*
11 36 24 19
(12) (40) (27) (21)
Values are shown as number (percent) or median (range). * One patient with two synchronous primaries (oral cavity and hypopharynx).
22). After induction chemotherapy, clinical and radiographic evaluations were used to assess treatment response before starting RT. Patients with progressive disease were treated with surgery; all others received concurrent chemoradiotherapy with cisplatin (20 mg/m2 given Monday, Wednesday, and Friday) and continuous infusion 5-FU (600 mg/m2/day for 96 hours per cycle) in Weeks 1 and 5 of RT. Patients in the OSP3 study (n Z 54) were randomized to receive the above-described regimen either alone or with tirapazamine (TPZ). TPZ was administered on Days 1, 22, 43, 45, 47, 71, 73, and 75 at a dosage of 300e330 mg/m2 for the induction phase and 160e260 mg/m2 for the concurrent phase. The addition of TPZ did not improve nodal response or any other outcome endpoints; the result of that study has been previously published (13). The RT was delivered to a total dose of 66 to 70 Gy in 2-Gy fractions using parallel opposed fields to cover the prechemotherapy tumor volume and bilateral upper necks. An anteroposterior supraclavicular field was used to treat the lower neck. The dose to the supraclavicular region was 50 Gy in 2-Gy fractions prescribed at the depth of 3 cm. Photons (4 megavolts)
Treatment Treatment details have been previously described (13) and are summarized in Fig. 1. All patients received two cycles of induction chemotherapy with cisplatin (100 mg/m2/day on Days 1 and 22) and 5-fluorouracil (FU) (continuous infusion of 1,000 mg/m2/day for 120 hours per cycle starting on Days 1 and
Fig. 1. Treatment schema. OSP Z Organ Sparing Protocol; SCCA Z squamous cell carcinoma; 5-FU Z 5-fluorouracil; RT Z radiation; TPZ Z tirapazamine.
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were used to treat the primary tumor and the regional lymph nodes. Electrons were used to boost the posterior neck and the involved lymph nodes. Patients treated according to the OSP3 protocol also received a single dose of 5 Gy delivered via 9- to 16MeV electrons to the largest nodal mass before treatment to perform a comet assay as part of a correlative analysis (14). At 50 Gy, all sites were reassessed for response using physical examination, direct fiberoptic evaluation, and CT or MRI. Patients with a clinical complete response (cCR) at the primary site and the neck completed RT to a dose 66 Gy to the primary site and the involved lymph nodes; patients with a cCR at the primary site but a clinical partial response (cPR) at the neck completed RT to the primary site followed by a PND. Neck cCR was defined as no palpable lymph nodes on physical examination and no lymph nodes with maximum cross-sectional diameter of >1.0 cm on CT or MRI. Neck cPR was defined as anything less than a cCR, and such patients were treated with a PND.
Follow-up Patients were followed up monthly for the first year, every 2 months for the second year, every 3 months for the third year, every 6 months for the fourth and fifth years, and yearly thereafter. Imaging studies of the head and neck region were performed at 2 months, 6 months, and 1 year after RT and as clinically indicated. Chest x-rays were obtained every 6 months for 2 years and yearly thereafter.
Statistical analysis All statistical analyses were performed using Stat View, v5.0.1 (SAS Institute Inc., Cary, NC). Disease-free survival (DFS) and overall survival (OS) rates, calculated from the date of diagnosis, were determined using the Kaplan-Meier product-limit method. All sites of recurrence and all deaths, regardless of cause, were coded as events to calculate the DFS rates; otherwise, patients were censored at the time of their last follow-up. Death from all causes was recorded for OS. Log-rank test and univariate Cox proportional hazard regression were used to assess categorical and
International Journal of Radiation Oncology Biology Physics continuous variables, respectively. Categorical outcomes were compared using the two-tailed Fisher’s exact test.
Results Neck response and patterns of failure Overall, 62% (n Z 56) of the patients achieved a cCR in the neck. Of the 56 patients with a cCR, 8 patients underwent a neck dissection, although this neck dissection was not according to protocol. All 8 patients had a pCR, and none have had a recurrence. Of the remaining 48 cCR patients whose necks were observed, only 1 patient (2%) had an isolated neck failure. Thirteen patients (23%) in the cCR group have experienced relapse (Fig. 2A). Five patients had neck failures as a component of their recurrence [neck and primary (n Z 2); neck, primary, and distant (n Z 1); neck only (n Z 1); neck and distant (n Z 1)]. Therefore, of the patients whose necks were observed after cCR, PND may have benefited 2 of 48 patients (4%) (Fig. 2A, shown in gray): the patient with an isolated neck recurrence and the patient with neck and distant failures, if we are to assume that the neck disease was the source of seeding for the distant metastases. Five patients had distant failures without a primary site or neck recurrence. Six patients had a primary site recurrence as a component of their relapse. Thirty-four patients (38%) had a cPR in the neck. Four patients had rapid disease progression during treatment and died without any salvage therapy. The remaining 30 patients were treated with PND, resulting in a pCR rate of 53% (n Z 16). Two of the 16 patients (13%) with a pCR ultimately experienced relapse [distant metastases only (n Z 1); primary and neck recurrence (n Z 1)]. Seven of 14 patients (50%) with a pPR had recurrences, including 3 patients who had neck failure as a component of their recurrence (primary and neck failure (n Z 2); isolated neck recurrence (n Z 1)]. (Fig. 2B). Included in this series were 19 patients with N3 disease. Two patients had rapid disease progression during treatment and died. Ten of 19 (53%) achieved cCR in the neck and did not undergo a PND; 8 patients remain free of disease, and 2 patients experienced recurrence with distant metastases only. Seven of 19
Fig. 2. Outcomes and patterns of failure for patients with a neck cCR (A) or cPR (B) after chemoradiotherapy. In gray are patients who may have benefited from a PND. cPR Z clinical partial response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response; LN Z lymph node; DM Z distant metastases.
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patients (37%) with less than cCR in the neck received PNDs, resulting in 5 pCR and 2 pPR; all 7 patients remain free of disease. Therefore, none with N3 neck disease experienced nodal relapse. In total, 9 of 90 patients experienced failure in the neck, either as an isolated neck failure (n Z 2) or as a component of their overall disease recurrence (n Z 7) (Fig. 2A and 2B). The 5-year neck control rates for patients with cCR, cPR/pCR, and cPR/pPR were 90% (95% confidence interval [CI], 94e81), 93% (95% CI, 106e81), and 78% (95% CI, 100e56), respectively (p Z 0.36) (Fig. 3). The p values for pairwise comparison of neck control rates between cCR vs. cPR/pCR, cCR vs. cPR/pPR, and cCR vs. cPR/pCR were 0.73, 0.27, and 0.22, respectively.
Disease-free survival and overall survival Fig. 4. Kaplan-Meier plot of disease free survival: ｘ, cPR followed by PND with no residual disease (cPR/pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response; DFS Z disease-free survival.
The median follow-up duration for all and living patients were 5.4 years (range, 0.6e16.3 years) and 8.3 years (range, 1.5e16.3 years), respectively. The 5-year DFS rates for cCR, cPR/pCR, and cPR/pPR groups were 53% (95% CI, 66e39), 75% (95% CI, 96e54), and 42% (95% CI, 68e15), respectively (p Z 0.04) (Fig. 4). The p values for pairwise comparison of DFS were as follows: cCR vs. cPR/pCR, 0.065; cCR vs. cPR/pPR, 0.010; cCR vs. cPR/pCR, 0.23. Likely because of harboring of subclinical disease, patients in the cCR group had a trend for lower DFS than did the cPR/pCR group (p Z 0.065); however, most of the recurrences involved primary or distant sites but not the neck. Fifty-one of 90 patients (57%) had died. The median overall survival time was 8.2 years. The 5-year Kaplan-Meier OS rate was 64% (95% CI, 74e54). The 5-year OS rates for the cCR, cPR/pCR, and cPR/pPR groups were 68% (95% CI, 81e55), 81% (95% CI, 100e62), and 48% (95% CI, 75e21) (p Z 0.012) (Fig. 5). The p values for pairwise comparison of OS were as follows: cCR vs. cPR/pCR, 0.034 (favoring the latter); cCR vs. cPR/pPR, 0.0054 (favoring the former); and cCR vs. cPR/pCR, 0.11. There were no differences in the outcomes between the OSP2 and OSP3 groups. The 5-year DFS rates for the OSP2 and OSP3 groups were 52% (95% CI, 69e36) and 53% (95% CI, 67e39),
respectively (p Z 0.95); the 5-year OS rates were 55% (95% CI, 72e39) and 70% (95% CI, 83e58), respectively (p Z 0.92). The cCR rates of patients in the OSP2 and OSP3 protocols were 58% and 65%, respectively (p Z 0.7). The pCR rates for patients with cPR undergoing PND were 45% and 58% for the OSP2 and OSP3 groups, respectively (p Z 0.6).
Fig. 3. Kaplan-Meier plot of neck control: ｘ, cPR followed by PND with no residual disease in surgical specimen ( cPR/pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response.
Fig. 5. Kaplan-Meier plot of overall survival: ｘ, cPR followed by PND with no residual disease (cPR/ pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response.
Discussion The optimal treatment of patients with advanced nodal disease after chemoradiotherapy is controversial. Recommendation of PND regardless of clinical response (4) is supported by the high rates of residual disease observed in PND surgical specimens (5,
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15) and the data showing improved regional control and survival with PND (6e8, 15). The downside of such an approach is the overtreatment of patients. A PND would benefit only patients with isolated neck recurrence. For patients whose cancer does not recur or for whom recurrence involves the primary and/or distant sites, PND is needless and would only add to morbidity. First, is PND necessary for patients with N2 or N3 neck disease who achieve a cCR in the neck after chemoradiation? The basis for recommending observation, deferring a PND, includes low rates (0e14%) of isolated neck recurrences after a cCR (12) and studies reporting a lack of regional control or OS benefit with the addition of a PND to patients with a cCR (6, 11). By contrast, the reported superior rates of regional control (7), DFS, and OS seen in some series with the addition of PND after a cCR have raised the question about the potential benefit of PND. In a study of patients with N2eN3 disease achieving a cCR after concurrent chemoradiation, the 4-year DFS (75% vs. 53%) and OS (77% vs. 50%) rates were higher for patients treated with PND vs. observation, respectively (8). Moreover, given that salvage treatments for isolated neck recurrence are associated with poor local-regional control and survival and higher toxicity (16, 17), some recommend PND for patients with N2 and N3 disease, regardless of response. The role of PND for patients with N3 neck disease is even more controversial (12). In a study of 70 patients with N3 neck disease treated with chemoradiotherapy, patients with cPR plus PND had improved DFS compared to those with a cCR followed by observation (5). Similar results were reported in another study where the addition of PND resulted in a trend toward improved PFS and OS rates in 27 patients with N3 disease (6). Patients in both of those studies were treated with concurrent chemoradiotherapy; there are few data assessing the role of PND after sequential chemoradiotherapy. To address these questions, we reviewed patients with N2 and N3 neck disease treated with sequential chemoradiotherapy in two prospective protocols at our institution. Our results are in agreement with those of previous studies reporting a low risk of isolated neck failure after a cCR (12). Moreover, based on the patterns of failure (Fig. 2A), PND would have definitely benefited only 1 patient (i.e., patient with an isolated neck recurrence), and possibly another (i.e., a patient with neck and distant failures, if we are to assume that the neck disease was the source of seeding for the distant metastases). In the publication by Brizel et al. (8), the addition of PND to a cCR after concurrent chemoradiotherapy improved neck control, DFS, and OS. Bearing in mind the many caveats of comparing two retrospective studies and noting the differences in treatment regimens (concurrent vs. sequential), the 4-year DFS and OS rates for cCR patients observed in our series of 69% and 74%, respectively, are comparable the cCR plus PND group of the series by Brizel et al. (75% and 77%, respectively), suggesting that similar outcomes can be reached without PND. The DFS and OS survival rates in the present series were superior for the patients in the cPR/pCR group compared with the cCR group (p Z 0.065 for DFS and 0.034 for OS comparisons). Nevertheless, the patterns of failure do not support the addition of PND to the cCR group. First, for the 6 patients observed after cCR who experienced failure at the primary site, PND would not have prevented primary site recurrence. Second, the 5 patients in the cCR group with distant metastases-only failures were likely harboring subclinical metastatic disease; therefore, PND would have provided no benefit. Therefore, on the basis of the low rate of neck recurrence and the patterns of failure,
International Journal of Radiation Oncology Biology Physics we do not recommend a PND in the setting of cCR, regardless of the initial nodal status. Second, how should patients with less than a cCR after chemoradiotherapy be treated? Of the 30 patients in our series with neck cPR treated with a PND, residual disease was found in 47% of the patients. Therefore, patients with cPR should proceed to a PND because a neck dissection for incomplete response has been shown to improve regional control (18). Residual disease, as shown by pathologic examination, has an important prognostic value because such patients have significantly worse DFS and OS (Figs. 4 and 5). Half of the patients in our series with pPR ultimately experienced cancer recurrence. Therefore, more aggressive therapy is needed for this group of patients. The Eastern Cooperative Oncology Group is developing a protocol to evaluate an irreversible epidermal growth factor receptor inhibitor to treat patients with pathologically proven residual neck disease (C. Chung, Johns Hopkins personal communication 2011). Additional research to develop novel therapeutic agents is needed. Human papillomavirus (HPV)dassociated head-and-neck cancers have been shown to have a better prognosis (19). Given the patient age and the treatment era of our series, we suspect that the majority of patients in this series were likely HPV negative. However, the majority of patients in our series were treated when HPV biomarkers were not routinely checked; thus, we cannot determine whether there is any prognostic value of tumor HPV status on the role of PND. Additional research is needed to improve the assessment of treatment response. Almost half of the patients with a cPR in our series had no residual disease as shown on pathologic specimens. Likewise, others have reported a positive predictive value of 29e44% of a cPR compared with pathologic response (5, 8). These data suggest that the combination of clinical examination and CT or MRI scans is often inadequate to determine when a cPR is truly a pPR. The present study was conducted during an era when posttreatment positron emission tomography (PET)-CT scans were not routinely obtained at our institution. Although the use of PET-CT scans has shown promise in some small studies, the results from a large, prospective, multicenter study evaluating the role of PET-CT performed 8 to10 weeks after RT plus chemotherapy was disappointing, with reported sensitivity, specificity, positive predictive value, and negative predictive value figures of 53%, 65%, 44%, and 73%, respectively; the authors of the study concluded that PET-CT is “not a reliable indicator of residual nodal disease and should not be used to determine the need for ND” (20). Another study reported similarly poor outcomes when postchemoradiation PET results were compared with pathologic findings (sensitivity of 45% and negative predictive value of 14%) (21). Advances in imaging techniques may help identify those patients with a cPR for whom a PND can be omitted. Until then, we recommend that patients achieving less than a cCR after chemoradiation proceed to PND.
Conclusions In our experience, patients with N2eN3 neck nodes who have achieved a clinical and radiographic complete response in the neck after chemoradiotherapy, a PND would have benefited only 4% of the patients and is, therefore, not routinely recommended. Patients achieving less than a cCR should be treated with a PND. Residual tumor in the neck dissection specimen is associated with poor DFS and OS; therefore, intensification of therapy is
Volume 83 Number 3 2012 recommended. Additional prospective studies using novel imaging modalities are needed to better assess treatment response.
References 1. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324:1685e1690. 2. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890e899. 3. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091e2098. 4. Pfister DG, Laurie SA, Weinstein GS, et al. American Society of Clinical Oncology clinical practice guideline for the use of larynxpreservation strategies in the treatment of laryngeal cancer. J Clin Oncol 2006;24:3693e3704. 5. Igidbashian L, Fortin B, Guertin L, et al. Outcome with neck dissection after chemoradiation for N3 head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2010;77:414e420. 6. Argiris A, Stenson KM, Brockstein BE, et al. Neck dissection in the combined-modality therapy of patients with locoregionally advanced head and neck cancer. Head Neck 2004;26:447e455. 7. Adelstein DJ, Saxton JP, Rybicki LA, et al. Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: Mature results from a single institution. J Clin Oncol 2006;24:1064e1071. 8. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced headand-neck cancer. Int J Radiat Oncol Biol Phys 2004;58:1418e1423. 9. 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;31:465e469. 10. 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;30:737e742.
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11. Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck dissection for lymph node-positive head and neck cancer: The use of computed tomography to manage the neck. J Clin Oncol 2006;24: 14211427. 12. Wee JT, Anderson BO, Corry J, et al. Management of the neck after chemoradiotherapy for head and neck cancers in Asia: Consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009; 10:1086e1092. 13. Le QT, Taira A, Budenz S, et al. Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable Stage IV head and neck squamous cell carcinomas. Cancer 2006;106:1940e1949. 14. Le QT, Kovacs MS, Dorie MJ, et al. Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2003;56: 375e383. 15. Frank DK, Hu KS, Culliney BE, et al. Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer. Laryngoscope 2005;115:1015e1020. 16. Mabanta SR, Mendenhall WM, Stringer SP, et al. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck 1999; 21:591e594. 17. Liauw SL, Amdur RJ, Morris CG, et al. Isolated neck recurrence after definitive radiotherapy for node-positive head and neck cancer: Salvage in the dissected or undissected neck. Head Neck 2007;29: 715e719. 18. Su CK, Bhattacharya J, Wang CC. Role of neck surgery in conjunction with radiation in regional control of node-positive cancer of the oropharynx. Am J Clin Oncol 2002;25:109e116. 19. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363: 24e35. 20. Waldron JN, Gilbert RW, Eapen L, et al. Results of an Ontario Clinical Oncology Group (OCOG) prospective cohort study on the use of FDG PET/CT to predict the need for neck dissection following radiation therapy of head and neck cancer (HNC). 2011 ASCO Annual Meeting. Chicago, IL; 2011. p. 5504. 21. Rogers JW, Greven KM, McGuirt WF, et al. Can post-RT neck dissection be omitted for patients with head-and-neck cancer who have a negative PET scan after definitive radiation therapy? Int J Radiat Oncol Biol Phys 2004;58:694e697.
Radiation Oncology biology
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Clinical Investigation: Head and Neck Cancer
A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy Scott G. Soltys, M.D.,* Clara Y.H. Choi, M.D., Ph.D.,y Willard E. Fee, M.D.,z Harlan A. Pinto, M.D.,x,{ and Quynh-Thu Le, M.D.* Departments of *Radiation Oncology, yNeurosugery, zOtolaryngology, and xMedical Oncology, Stanford University Medical Center, Stanford; and {Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA Received Apr 26, 2011, and in revised form Jul 13, 2011. Accepted for publication Jul 29, 2011
Summary This study evaluated the role of a planned neck dissection (PND) in patients with N2-3 neck disease treated on prospective organ preservation protocols using chemoradiotherapy. Those with a neck cCR after chemoradiation were observed, all others received a PND. Patterns of failure suggest a PND would have benefited only 4% of those who achieved a neck cCR and cannot, therefore, be recommended. Nearly half of those with a clinical partial response had residual tumor in the neck dissection specimen and a PND should routinely follow.
Purpose: To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2eN3 nodal disease. Methods and Materials: We reviewed 90 patients with N2eN3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed. Results: The median follow-up durations for living and all patients were 8.3 years (range, 1.5e 16.3 year) and 5.4 years (range, 0.6e16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n Z 2); neck, primary, and distant (n Z 1); neck only (n Z 1); neck and distant (n Z 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n Z 1); neck and distant failure (n Z 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n Z 30) was 53%. The 5-year neck control rates after cCR, cPR/pCR, and cPR/pPR were 90%, 93%, and 78%, respectively (p Z 0.36). The 5-year disease-free survival rates for the cCR, cPR/pCR, and cPR/pPR groups were 53%, 75%, and 42%, respectively (p Z 0.04). Conclusion: In our series, patients with N2eN3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response. Ó 2012 Elsevier Inc. Keywords: Head-and-neck cancer, Chemoradiation, Neck dissection, Sequential
Reprint requests to: Scott G. Soltys, M.D., Stanford University Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847. Tel: (650) 724-1569; Fax: (650) 725-8231; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 83, No. 3, pp. 994e999, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.07.042
S. G. Soltys and C. Y. H. Choi contributed equally to this study. Conflict of interest: none.
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Introduction Treatment with chemoradiotherapy for locally advanced headand-neck cancer results in similar survival rates as surgery plus adjuvant radiation (RT) (1e3) and allows for organ preservation. The optimal management of N2 and N3 neck disease after chemoradiotherapy is controversial. The American Society of Clinical Oncology practice guideline for larynx preservation recommends surgical treatment of the neck for patients with N2 or N3 disease, regardless of response (4). This is supported by some literature demonstrating locoregional control and survival benefits with the addition of planned neck dissection (PND) (5e8). Even in the setting of a clinical complete response (cCR) after chemoradiation, PND has been shown to improve disease-free survival (DFS) and overall survival (OS) compared with observation in some series (8). Alternatively, considering the potential morbidity of a PND and that it will only benefit those with an isolated neck failure, some have questioned the value of routine PND (9e11). Based on the low rates of isolated neck recurrence after a cCR to chemoradiation, some investigators recommend observation for patients achieving a cCR (12). Similarly, the National Comprehensive Cancer Network guidelines v2.2011 recommend observation for an imaging negative neck. The purpose of this study was to evaluate the role of PND in head-and-neck squamous cell carcinoma (SCCA) patients with N2 and N3 neck disease treated with sequential chemoradiotherapy (defined as induction chemotherapy followed by concurrent chemoradiotherapy). We retrospectively reviewed the outcomes in patients treated on two prospective sequential chemoradiotherapy organ preservation protocols to assess whether PND can be omitted in such patients.
Methods and Materials Patients The records of 90 head and neck SCCA patients with N2 and N3 neck disease treated at Stanford University Medical Center between 1991 and 2001 on two prospective organ preservation sequential chemoradiotherapy protocols (OSP2 (Organ Sparing Protocol 2) and OSP3) (13) were reviewed. Patient characteristics are shown in Table 1. Patients with nasopharynx and paranasal sinus primaries were excluded. Patients with unknown primary cancers with metastases to cervical lymph nodes were eligible because the primary endpoint of the study was the nodal response rate. Before treatment, all patients underwent a complete history and physical examination, laboratory studies (complete blood count, comprehensive chemistry panel, and 24-hour creatinine clearance), imaging studies (magnetic resonance imaging [MRI] or computed tomography [CT] of the head and neck sites, chest xray), and baseline audiograms.
Planned neck dissection after sequential chemoradiotherapy Table
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Patient characteristics
Age (y) Median (range) Sex M F Primary site Oral cavity* Oropharynx Larynx Hypopharynx* Unknown primary T stage T0 T1 T2 T3 T4 N stage N2a N2b N2c N3
58 (39e80) 76 (84) 14 (16) 3 60 8 18 2
(3) (67) (9) (20) (2)
2 10 28 14 37
(2) (11) (31)* (15) (41)*
11 36 24 19
(12) (40) (27) (21)
Values are shown as number (percent) or median (range). * One patient with two synchronous primaries (oral cavity and hypopharynx).
22). After induction chemotherapy, clinical and radiographic evaluations were used to assess treatment response before starting RT. Patients with progressive disease were treated with surgery; all others received concurrent chemoradiotherapy with cisplatin (20 mg/m2 given Monday, Wednesday, and Friday) and continuous infusion 5-FU (600 mg/m2/day for 96 hours per cycle) in Weeks 1 and 5 of RT. Patients in the OSP3 study (n Z 54) were randomized to receive the above-described regimen either alone or with tirapazamine (TPZ). TPZ was administered on Days 1, 22, 43, 45, 47, 71, 73, and 75 at a dosage of 300e330 mg/m2 for the induction phase and 160e260 mg/m2 for the concurrent phase. The addition of TPZ did not improve nodal response or any other outcome endpoints; the result of that study has been previously published (13). The RT was delivered to a total dose of 66 to 70 Gy in 2-Gy fractions using parallel opposed fields to cover the prechemotherapy tumor volume and bilateral upper necks. An anteroposterior supraclavicular field was used to treat the lower neck. The dose to the supraclavicular region was 50 Gy in 2-Gy fractions prescribed at the depth of 3 cm. Photons (4 megavolts)
Treatment Treatment details have been previously described (13) and are summarized in Fig. 1. All patients received two cycles of induction chemotherapy with cisplatin (100 mg/m2/day on Days 1 and 22) and 5-fluorouracil (FU) (continuous infusion of 1,000 mg/m2/day for 120 hours per cycle starting on Days 1 and
Fig. 1. Treatment schema. OSP Z Organ Sparing Protocol; SCCA Z squamous cell carcinoma; 5-FU Z 5-fluorouracil; RT Z radiation; TPZ Z tirapazamine.
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were used to treat the primary tumor and the regional lymph nodes. Electrons were used to boost the posterior neck and the involved lymph nodes. Patients treated according to the OSP3 protocol also received a single dose of 5 Gy delivered via 9- to 16MeV electrons to the largest nodal mass before treatment to perform a comet assay as part of a correlative analysis (14). At 50 Gy, all sites were reassessed for response using physical examination, direct fiberoptic evaluation, and CT or MRI. Patients with a clinical complete response (cCR) at the primary site and the neck completed RT to a dose 66 Gy to the primary site and the involved lymph nodes; patients with a cCR at the primary site but a clinical partial response (cPR) at the neck completed RT to the primary site followed by a PND. Neck cCR was defined as no palpable lymph nodes on physical examination and no lymph nodes with maximum cross-sectional diameter of >1.0 cm on CT or MRI. Neck cPR was defined as anything less than a cCR, and such patients were treated with a PND.
Follow-up Patients were followed up monthly for the first year, every 2 months for the second year, every 3 months for the third year, every 6 months for the fourth and fifth years, and yearly thereafter. Imaging studies of the head and neck region were performed at 2 months, 6 months, and 1 year after RT and as clinically indicated. Chest x-rays were obtained every 6 months for 2 years and yearly thereafter.
Statistical analysis All statistical analyses were performed using Stat View, v5.0.1 (SAS Institute Inc., Cary, NC). Disease-free survival (DFS) and overall survival (OS) rates, calculated from the date of diagnosis, were determined using the Kaplan-Meier product-limit method. All sites of recurrence and all deaths, regardless of cause, were coded as events to calculate the DFS rates; otherwise, patients were censored at the time of their last follow-up. Death from all causes was recorded for OS. Log-rank test and univariate Cox proportional hazard regression were used to assess categorical and
International Journal of Radiation Oncology Biology Physics continuous variables, respectively. Categorical outcomes were compared using the two-tailed Fisher’s exact test.
Results Neck response and patterns of failure Overall, 62% (n Z 56) of the patients achieved a cCR in the neck. Of the 56 patients with a cCR, 8 patients underwent a neck dissection, although this neck dissection was not according to protocol. All 8 patients had a pCR, and none have had a recurrence. Of the remaining 48 cCR patients whose necks were observed, only 1 patient (2%) had an isolated neck failure. Thirteen patients (23%) in the cCR group have experienced relapse (Fig. 2A). Five patients had neck failures as a component of their recurrence [neck and primary (n Z 2); neck, primary, and distant (n Z 1); neck only (n Z 1); neck and distant (n Z 1)]. Therefore, of the patients whose necks were observed after cCR, PND may have benefited 2 of 48 patients (4%) (Fig. 2A, shown in gray): the patient with an isolated neck recurrence and the patient with neck and distant failures, if we are to assume that the neck disease was the source of seeding for the distant metastases. Five patients had distant failures without a primary site or neck recurrence. Six patients had a primary site recurrence as a component of their relapse. Thirty-four patients (38%) had a cPR in the neck. Four patients had rapid disease progression during treatment and died without any salvage therapy. The remaining 30 patients were treated with PND, resulting in a pCR rate of 53% (n Z 16). Two of the 16 patients (13%) with a pCR ultimately experienced relapse [distant metastases only (n Z 1); primary and neck recurrence (n Z 1)]. Seven of 14 patients (50%) with a pPR had recurrences, including 3 patients who had neck failure as a component of their recurrence (primary and neck failure (n Z 2); isolated neck recurrence (n Z 1)]. (Fig. 2B). Included in this series were 19 patients with N3 disease. Two patients had rapid disease progression during treatment and died. Ten of 19 (53%) achieved cCR in the neck and did not undergo a PND; 8 patients remain free of disease, and 2 patients experienced recurrence with distant metastases only. Seven of 19
Fig. 2. Outcomes and patterns of failure for patients with a neck cCR (A) or cPR (B) after chemoradiotherapy. In gray are patients who may have benefited from a PND. cPR Z clinical partial response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response; LN Z lymph node; DM Z distant metastases.
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patients (37%) with less than cCR in the neck received PNDs, resulting in 5 pCR and 2 pPR; all 7 patients remain free of disease. Therefore, none with N3 neck disease experienced nodal relapse. In total, 9 of 90 patients experienced failure in the neck, either as an isolated neck failure (n Z 2) or as a component of their overall disease recurrence (n Z 7) (Fig. 2A and 2B). The 5-year neck control rates for patients with cCR, cPR/pCR, and cPR/pPR were 90% (95% confidence interval [CI], 94e81), 93% (95% CI, 106e81), and 78% (95% CI, 100e56), respectively (p Z 0.36) (Fig. 3). The p values for pairwise comparison of neck control rates between cCR vs. cPR/pCR, cCR vs. cPR/pPR, and cCR vs. cPR/pCR were 0.73, 0.27, and 0.22, respectively.
Disease-free survival and overall survival Fig. 4. Kaplan-Meier plot of disease free survival: ｘ, cPR followed by PND with no residual disease (cPR/pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response; DFS Z disease-free survival.
The median follow-up duration for all and living patients were 5.4 years (range, 0.6e16.3 years) and 8.3 years (range, 1.5e16.3 years), respectively. The 5-year DFS rates for cCR, cPR/pCR, and cPR/pPR groups were 53% (95% CI, 66e39), 75% (95% CI, 96e54), and 42% (95% CI, 68e15), respectively (p Z 0.04) (Fig. 4). The p values for pairwise comparison of DFS were as follows: cCR vs. cPR/pCR, 0.065; cCR vs. cPR/pPR, 0.010; cCR vs. cPR/pCR, 0.23. Likely because of harboring of subclinical disease, patients in the cCR group had a trend for lower DFS than did the cPR/pCR group (p Z 0.065); however, most of the recurrences involved primary or distant sites but not the neck. Fifty-one of 90 patients (57%) had died. The median overall survival time was 8.2 years. The 5-year Kaplan-Meier OS rate was 64% (95% CI, 74e54). The 5-year OS rates for the cCR, cPR/pCR, and cPR/pPR groups were 68% (95% CI, 81e55), 81% (95% CI, 100e62), and 48% (95% CI, 75e21) (p Z 0.012) (Fig. 5). The p values for pairwise comparison of OS were as follows: cCR vs. cPR/pCR, 0.034 (favoring the latter); cCR vs. cPR/pPR, 0.0054 (favoring the former); and cCR vs. cPR/pCR, 0.11. There were no differences in the outcomes between the OSP2 and OSP3 groups. The 5-year DFS rates for the OSP2 and OSP3 groups were 52% (95% CI, 69e36) and 53% (95% CI, 67e39),
respectively (p Z 0.95); the 5-year OS rates were 55% (95% CI, 72e39) and 70% (95% CI, 83e58), respectively (p Z 0.92). The cCR rates of patients in the OSP2 and OSP3 protocols were 58% and 65%, respectively (p Z 0.7). The pCR rates for patients with cPR undergoing PND were 45% and 58% for the OSP2 and OSP3 groups, respectively (p Z 0.6).
Fig. 3. Kaplan-Meier plot of neck control: ｘ, cPR followed by PND with no residual disease in surgical specimen ( cPR/pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response.
Fig. 5. Kaplan-Meier plot of overall survival: ｘ, cPR followed by PND with no residual disease (cPR/ pCR); ￮, cCR; :, cPR followed by PND with residual disease (cPR/ pPR). cPR Z clinical partial response; cCR Z clinical complete response; PND Z planned neck dissection; pPR Z pathologic partial response; pCR Z pathologic complete response.
Discussion The optimal treatment of patients with advanced nodal disease after chemoradiotherapy is controversial. Recommendation of PND regardless of clinical response (4) is supported by the high rates of residual disease observed in PND surgical specimens (5,
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15) and the data showing improved regional control and survival with PND (6e8, 15). The downside of such an approach is the overtreatment of patients. A PND would benefit only patients with isolated neck recurrence. For patients whose cancer does not recur or for whom recurrence involves the primary and/or distant sites, PND is needless and would only add to morbidity. First, is PND necessary for patients with N2 or N3 neck disease who achieve a cCR in the neck after chemoradiation? The basis for recommending observation, deferring a PND, includes low rates (0e14%) of isolated neck recurrences after a cCR (12) and studies reporting a lack of regional control or OS benefit with the addition of a PND to patients with a cCR (6, 11). By contrast, the reported superior rates of regional control (7), DFS, and OS seen in some series with the addition of PND after a cCR have raised the question about the potential benefit of PND. In a study of patients with N2eN3 disease achieving a cCR after concurrent chemoradiation, the 4-year DFS (75% vs. 53%) and OS (77% vs. 50%) rates were higher for patients treated with PND vs. observation, respectively (8). Moreover, given that salvage treatments for isolated neck recurrence are associated with poor local-regional control and survival and higher toxicity (16, 17), some recommend PND for patients with N2 and N3 disease, regardless of response. The role of PND for patients with N3 neck disease is even more controversial (12). In a study of 70 patients with N3 neck disease treated with chemoradiotherapy, patients with cPR plus PND had improved DFS compared to those with a cCR followed by observation (5). Similar results were reported in another study where the addition of PND resulted in a trend toward improved PFS and OS rates in 27 patients with N3 disease (6). Patients in both of those studies were treated with concurrent chemoradiotherapy; there are few data assessing the role of PND after sequential chemoradiotherapy. To address these questions, we reviewed patients with N2 and N3 neck disease treated with sequential chemoradiotherapy in two prospective protocols at our institution. Our results are in agreement with those of previous studies reporting a low risk of isolated neck failure after a cCR (12). Moreover, based on the patterns of failure (Fig. 2A), PND would have definitely benefited only 1 patient (i.e., patient with an isolated neck recurrence), and possibly another (i.e., a patient with neck and distant failures, if we are to assume that the neck disease was the source of seeding for the distant metastases). In the publication by Brizel et al. (8), the addition of PND to a cCR after concurrent chemoradiotherapy improved neck control, DFS, and OS. Bearing in mind the many caveats of comparing two retrospective studies and noting the differences in treatment regimens (concurrent vs. sequential), the 4-year DFS and OS rates for cCR patients observed in our series of 69% and 74%, respectively, are comparable the cCR plus PND group of the series by Brizel et al. (75% and 77%, respectively), suggesting that similar outcomes can be reached without PND. The DFS and OS survival rates in the present series were superior for the patients in the cPR/pCR group compared with the cCR group (p Z 0.065 for DFS and 0.034 for OS comparisons). Nevertheless, the patterns of failure do not support the addition of PND to the cCR group. First, for the 6 patients observed after cCR who experienced failure at the primary site, PND would not have prevented primary site recurrence. Second, the 5 patients in the cCR group with distant metastases-only failures were likely harboring subclinical metastatic disease; therefore, PND would have provided no benefit. Therefore, on the basis of the low rate of neck recurrence and the patterns of failure,
International Journal of Radiation Oncology Biology Physics we do not recommend a PND in the setting of cCR, regardless of the initial nodal status. Second, how should patients with less than a cCR after chemoradiotherapy be treated? Of the 30 patients in our series with neck cPR treated with a PND, residual disease was found in 47% of the patients. Therefore, patients with cPR should proceed to a PND because a neck dissection for incomplete response has been shown to improve regional control (18). Residual disease, as shown by pathologic examination, has an important prognostic value because such patients have significantly worse DFS and OS (Figs. 4 and 5). Half of the patients in our series with pPR ultimately experienced cancer recurrence. Therefore, more aggressive therapy is needed for this group of patients. The Eastern Cooperative Oncology Group is developing a protocol to evaluate an irreversible epidermal growth factor receptor inhibitor to treat patients with pathologically proven residual neck disease (C. Chung, Johns Hopkins personal communication 2011). Additional research to develop novel therapeutic agents is needed. Human papillomavirus (HPV)dassociated head-and-neck cancers have been shown to have a better prognosis (19). Given the patient age and the treatment era of our series, we suspect that the majority of patients in this series were likely HPV negative. However, the majority of patients in our series were treated when HPV biomarkers were not routinely checked; thus, we cannot determine whether there is any prognostic value of tumor HPV status on the role of PND. Additional research is needed to improve the assessment of treatment response. Almost half of the patients with a cPR in our series had no residual disease as shown on pathologic specimens. Likewise, others have reported a positive predictive value of 29e44% of a cPR compared with pathologic response (5, 8). These data suggest that the combination of clinical examination and CT or MRI scans is often inadequate to determine when a cPR is truly a pPR. The present study was conducted during an era when posttreatment positron emission tomography (PET)-CT scans were not routinely obtained at our institution. Although the use of PET-CT scans has shown promise in some small studies, the results from a large, prospective, multicenter study evaluating the role of PET-CT performed 8 to10 weeks after RT plus chemotherapy was disappointing, with reported sensitivity, specificity, positive predictive value, and negative predictive value figures of 53%, 65%, 44%, and 73%, respectively; the authors of the study concluded that PET-CT is “not a reliable indicator of residual nodal disease and should not be used to determine the need for ND” (20). Another study reported similarly poor outcomes when postchemoradiation PET results were compared with pathologic findings (sensitivity of 45% and negative predictive value of 14%) (21). Advances in imaging techniques may help identify those patients with a cPR for whom a PND can be omitted. Until then, we recommend that patients achieving less than a cCR after chemoradiation proceed to PND.
Conclusions In our experience, patients with N2eN3 neck nodes who have achieved a clinical and radiographic complete response in the neck after chemoradiotherapy, a PND would have benefited only 4% of the patients and is, therefore, not routinely recommended. Patients achieving less than a cCR should be treated with a PND. Residual tumor in the neck dissection specimen is associated with poor DFS and OS; therefore, intensification of therapy is
Volume 83 Number 3 2012 recommended. Additional prospective studies using novel imaging modalities are needed to better assess treatment response.
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