The Role of Neck Dissection Following Definitive Chemoradiation

ABSTRACT: The presence of regional nodal metastases represents a significant adverse prognostic factor for patients with squamous cell carcinoma of the head and neck. Early-stage head and neck cancers, localized to the primary site without regional lymph node metastases have excellent cure rates with either surgery or radiation therapy. The presence of regional metastases results in cure rates that are approximately half of those obtainable in early-stage disease. Therefore, due to the significant adverse impact of neck metastases on prognosis, the treatment of the neck remains a vital part of the decision-making process in determining therapy for head and neck cancer.

Over the past decade, the role of chemoradiotherapy in the definitive management of head and neck squamous cell carcinoma has been extensively studied. Several different sequences of treatment modalities have been explored, including neoadjuvant chemotherapy followed by definitive radiotherapy, alternating chemotherapy with radiotherapy, and concurrent chemoradiation. Concurrent chemoradiation has emerged as a preferred treatment option and has been shown to yield tumor response rates that are higher than the other combinations, while simultaneously achieving the goal of organ preservation.

Several phase III randomized trials and meta-analyses have shown that platinum-based concomitant chemotherapy and radiotherapy are superior to conventional radiotherapy alone in improving clinical response rates at the primary site, local and regional control, relapse-free survival, and overall survival in locally advanced disease.[1-5] However, despite the improved benefit of concurrent chemoradiation, there is no consensus in the literature on the optimal management of neck metastases in a concurrentapproach. In addition, because of the paucity of data, a number of controversies persist regarding optimal treatment of the neck in concurrent chemoradiation, and this has reopened the debate on the role of a planned neck dissection in these patients to control regional node metastases. The main question that needs to be addressed is: Should a neck dissection be a planned component in the concurrent chemoradiotherapy strategy?

Management Considerations

The initial pretreatment stage of the neck is important in deciding the appropriate management of the neck after definitive chemoradiation. Studies from The University of Texas M. D. Anderson Cancer Center in the 1970s showed a relationship betweenthe size of nodal burden and response to radiation.[6] For example, occult neck metastases or a single node less than 3 cm in diameter can generally be sterilized with chemoradiation therapy. Therefore, patients with low-volume (N1) neck disease have very high rates of control in the neck[7] and do not require neck dissection unless there is clinical evidence of persistent palpable disease after chemoradiation. The risk of neck failure climbs steadily with increasing neck node stage and tumor burden. Due to this risk,patients with stage N2 or N3 neck initially treated nonsurgically, have historically undergone planned neck dissection after chemoradiotherapy.

The site of the primary tumor may be equally important in therapeutic decision-making: Metastatic nodal disease from tumors of certain sites such as the nasopharynx and the tonsil are known to be exquisitely sensitive to radiation therapy. A planned neck dissection following complete response to chemoradiation may not be particularly beneficial in these patients with tumors arising from the Waldeyer's ring.

The decision for neck dissection following chemoradiation is clear when patients have residual neck disease.[ 8] However, controversy surrounds neck dissection in patients with a complete clinical response to chemoradiation. Recently, some authors have questioned whether planned neck dissection after chemoradiotherapy is necessary for patients with a complete clinical response, because a large percentage of these patients have negative neck dissection specimens on histologic examination.[9,10]

This controversy has led to institutional differences in the management of the neck after chemoradiation. Proponents of neck dissection argue that the procedure reduces the regional failure rate and may improve the cause-specific survival rate. In addition, salvage surgery in the event of recurrence is unlikely to succeed. Proponents of observation argue that the probability of an isolated recurrence in the neck is low, and many patients needlessly undergo neck dissection to benefit a few. However, no randomized trials have addressed the question specifically.

Role of Neck Dissection

The Postirradiated Neck

The purpose of the planned neck dissection in patients with N2/3 neck disease undergoing radiation or chemoradiation is to maximize the probability of achieving regional control. Parson et al reported improved neck control rates in patients with N2 and N3 disease treated with radiotherapy followed by neck dissectionvs radiotherapy alone.[11] In a large series of patients with advanced neck disease treated with radical radiotherapy alone at the Institut Curie, Dubray et al reported overall 3-year actuarial neck failure rates of 33% for N2 (n = 103) and 45% for N3 (n = 699).[12] However, in the same series, the incidence of isolated neck failure was only 7%. One can conclude from these reports that planned neck dissection contributes to neck control in unselected N2 and N3 patients treated with radiation or chemoradiation, but its exact role remains undefined.[12]

The Postchemoradiated Neck

The main controversy in the literature is whether patients could be selected for neck dissection following chemoradiation based on their response to treatment. In other words, can neck dissection be omitted in the subset of patients with N2/3 neck disease who achieve a complete response in the neck after concurrent chemoradiation?

• Residual Disease-Several studies have shown that patients with a complete response to chemoradiation clinically and radiographically may have microscopic residual disease in the neck. McHamm et al recently reviewed 109 patients with N2/3 disease treated with concurrent chemoradiation followed by neck dissection and found that 25% of the patients achieving a complete response in the neck had residual pathologic evidence of disease in the neck dissection specimen.[ 13] In addition, no clinical parameters could reliably predict for a pathologically positive neck or for those patients destined to have a recurrence in the neck, suggesting a role for neck dissection in all N2/3 patients.[13]

Similarly, Stenson et al reviewed 69 patients with advanced-stage head and neck cancer who underwent a neck dissection within 5 to 17 weeks after concurrent chemoradiotherapy.[ 14] Of these 69 patients, 24 (35%) had microscopic residual disease, and this was not correlated with clinical or radiographic response. Only one patient had recurrent disease in the neck after neck dissection, emphasizingthe importance of neck dissection after chemoradiation to remove residual viable tumor.

Wanebo et al reported a series of 43 patients treated with concurrent chemoradiotherapy for advancedstage head and neck squamous cell carcinoma. A planned neck dissection was performed 3 to 4 weeks after the completion of chemoradiotherapy; among patients with clinically N1-3 nodes prior to therapy, 9 (31%) of 29 had residual node involvement at neck dissection, and none of these patients had failure in the neck. The authors concluded that planned neck dissection is an essential component of aggressive chemoradiotherapy protocols to ensure and optimize tumor control in the neck.[15]

• Recurrence and Survival-The presence of pathologically positive nodal disease in neck dissection specimens after radiotherapy or concurrent chemoradiotherapy has been found to correlate with neck recurrence and survival probability. Lavertu et al evaluated 53 patients with N2/3 necks who had planned neck dissections after radiotherapy or concurrent chemoradiotherapy.[15] Of 53 patients with N2/3 disease, 35 underwent neck dissections, 18 of whom had a clinical complete response in the neck, with 17 achieving less than a complete response. Of the 18 patients with a complete response, 4 (22%) had viable tumor in the neck compared with 8 of 17 (47%) with less than a complete response. Disease recurred in 1 of the 35 necks after neck dissection; no recurrences occurred among the 18 patients with a complete response who underwent neck dissection, compared with 3 recurrences among 12 patients with a complete response but no neck dissection.

Disease-specific survival was not significantly affected by clinical response in the neck. However, among the N2/3 patients, pathologically positive neck disease was associated with a worse survival (6 of 12) compared with pathologically negative patients (4 of 23; P = .03). These data also support the use of planned neck dissection for management of clinicalneck disease. Furthermore, they demonstrated a lower rate of nodal recurrence following neck dissection, and the inability to salvage patients who had not undergone neck dissection.

Those who advocate limiting neck dissection only to patients with residual disease after initial chemoradiation believe that planned neck dissection in patients with a complete response results in many unnecessary neck dissections. In addition, several studies have reported that patients who have a complete response to radiation or chemoradiation, but do not undergo neck dissection, show a low rate of recurrent neck disease (11% to 25%).[7,16]

Armstrong et al reported a series of 54 node-positive patients treated with various regimens of induction chemotherapy followed by radiation alone or combined with a neck dissection. They reported 24 of 54 patients (44%) had a complete responseto induction chemotherapy, and 17 subsequently received radiation therapy alone. The neck remained controlled after irradiation in 16 (94%) of the 17 patients who did not undergo a neck dissection. Due to the high neck control rate in these patients, the authors recommended that patients with a complete response after chemoradiation need not undergo planned neck dissection.[7]

TABLE 1

Summary of Literature for Chemoradiation in Head and Neck Cancer Patients

Koch et al prospectively studied 22 patients with advanced head and neck cancer of the oropharynx, oral cavity, and hypopharynx entered into a concurrent chemotherapy/radiotherapy protocol.[17] All patients with > N2 disease were scheduled for planned neck dissections. Although 11 patients were entered with N2/3 disease, only six neck dissections were documented, and two of these were performed for salvage or palliation. The 2-year overall survival was estimated at 64%, and the disease-specific survival at 71%. Neck recurrence was shown in 5 (23%) of 22. Neck dissection was not documented in 7 of the 11 N2/3 patients, all of whom had no evidence of disease at 13- to 36-month follow-up. These authorsbelieve that neck dissection after organ preservation therapy is of uncertain value in this subgroup of patients.[17] A summary of the literature for chemoradiation is presented in Table 1.[16-20]

• Neck Failure/Pathologic Node Discrepancy-Interestingly, the rate of neck failure in these studies is lower than the incidence of pathologic nodes among the neck dissection specimens of patients who had a complete response to radiation therapy and underwent a neck dissection, suggesting to some that many of the pathologically positive necks did not contain viable cancer cells, or alternatively, that continued cell kill occurs for several weeks or months after chemoradiotherapy.

A recent study tried to distinguish the neck specimens with viable cancer cells from those without by studying Ki-67, a marker for dividing cancer cells. In a series of 17 neck dissection specimens, only 3 of 11 with histology positive for carcinoma demonstrated the presence of Ki-67, whereas many samples had extensive apoptosis, suggesting tumor demise.[21] These findings led to speculation that the difficulty in interpreting positive but nonviable tumor cells in lymph nodes in the neck may be responsible for the discrepancy in the rates of neck recurrence among various reports. It is also important to consider the timing of neck dissection and the interval at which the neck dissection is, therefore, examined for the presence of "residua" disease, because it appears that cell death continues to occur for many weeks following completion of treatment.

• Complications-Neck dissection after organ-preservation therapy is also not without complications and morbidity. Complication rates from neck dissections after concurrent chemoradiotherapy have been reported to range from 26% to 35% and have most often reflected impaired wound healing. However, Newman et al reported that postoperative complication rates after induction chemotherapy followed by concurrent chemoradiotherapy were similar to a control group for both major and minor complications.[22]

Similarly, Lavertu et al found that surgery following radiation or concurrent chemoradiation can be performed with an acceptable rate of major complications (7% after neck dissection for radiation only and 0% after neck dissection for chemoradiation).[ 18] Although the major complication rate is relatively low, the question remains as to whether this surgical morbidity is justified for all N2/3 patients, or is it reasonable to reserve surgery for those who recur despite an initial complete response in the neck?

Fallacy of Clinical Assessment in the Posttreatment Neck

Unfortunately, no diagnostic technique universally detects persistent nodal disease after concurrent chemoradiation. Clinical evaluation of the response to nonsurgical therapy is difficult. Posttreatment induration and fibrosis obscure accurate clinical assessment. Anatomic diagnostic imaging, such as computed tomography, magnetic resonance imaging, andultrasonography, all fall short of consistently demonstrating persistent or recurrent tumor following chemotherapy and radiation, given sequentially or concurrently. Biopsies to rule out residual tumor are also not helpful in the posttreatment setting. Biopsy specimens in a previously treated area may be falsely negative as a result of a sampling error that misses focally dispersed residual tumor.

The utility of less invasive biopsy techniques such as fine-needle aspiration may be even more difficult to rely on, since a specimen interpreted as negative for malignancy does not rule out the possibility of viable tumor. Previous studies have demonstrated the inadequacy of the evaluation of tumor response by clinical examination, and histologic evidence of residual disease.[ 19] The discrepancy between observed clinical response and histologic assessment of tumor persistence may, in part, be due to our present inability to distinguish viable tumor cells reliably on routine sectioning and hematoxylin-and-eosin staining. Ghosting of dead cells with residual squamous architecture may not be evident for weeks following radiation therapy. Therefore, a better way of identifying patients with residual disease who would benefit from a neck dissection is needed.

Identifying Residual Disease

Role of Positron-Emission Tomography

One potential way of improving the discrimination of clinical assessment is by functional imaging with positron-emission tomography (PET). 18-Fluorodeoxyglucose (FDG)-PET scanning has been shown to correlate with clinical response to concurrent chemoradiation before, during, and after therapy. Wong et al reviewed 143 patients with previously treated head and neck squamous cell carcinoma who underwent FDG-PET scan to detect recurrent disease and found this to be a highly sensitive method for detecting recurrent head and neck squamous cell carcinoma, with a 96% and 72% sensitivity and specificity, respectively.[ 23] Unfortunately, complete tumor response following chemoradchemoradiotherapy may take several weeks, and an FDG-PET scan may be falsely positive if it is performed too soon after the completion of treatment.[24]

Greven et al[25] evaluated 45 patients with head and neck cancer by FDG-PET scan before radiotherapy and serially after radiotherapy (1, 4, 12, and 24 months after radiotherapy). At 1 month after radiotherapy, the false-negative rate was 28%. The 4-month scans, although performed in a selected population, were more accurate. The ideal time to perform FDG-PET scans for the evaluation of residual disease has yet to be determined, but seems to be between 1 and 4 months. Further prospective studies are necessary, however, prior to the adoption of PET scanning as the standard of care in the evaluation of the neck following chemoradiation.

Role of Biomarkers

Given that anatomic imaging techniques are subpar in identifying residual neck disease, and that FDGPET is promising but not highly specific in the posttreatment setting, new molecular methods may represent the future of optimal patient assessment. Biologic markers such as neu, HSP27, p53, ki-67, and GST may be useful in predicting nodal failure after radical radiotherapy or chemoradiotherapy. For example, Fortin et al found that the presence of neu oncoprotein and the absence of HSP27 expression were associated with an increased rate of neck failure in patients treated with radiotherapy.[26] These markers, therefore, may predict the subgroup of patients who require posttreatment neck dissection.

This technology can be further expanded in the future by combining molecular markers with functional imaging, thereby allowing significantly improved assessment of the posttreated neck. Whether these technologies could be applied to surgical patients or to patients treated with chemoradiation remains to be demonstrated.

Risk of Observation in Patients With Complete Response to Chemoradiation

Unfortunately, reserving neck dissection for those with a regional recurrence may not be possible in the subset of patients who undergo radiotherapy or chemoradiotherapy, in light of an inherent difficulty in evaluating and following the neck recurrence in these patients and because salvage of recurrent disease in the neck is rarely successful. As discussed above, the currently employed methods for clinical assessment of residual or recurrent disease (palpation, radiographic imaging, and fine-needle aspiration) after chemoradiation are unreliable.[ 10,20] In addition, the detection of late recurrent disease in the neck after chemoradiation is extremely difficult due to fibrosis.

This difficulty in evaluating for recurrence has made salvage neck surgery less effective, and late recurrences in the neck are rarely surgically salvageable. McHamm et al were able to salvage only two of nine patients who developed regional failure after definitive chemoradiation, and all nine died of their disease.[13] Similarly, Mabanta et al reported that only 18 (35%) of 51 patients with nodal recurrence after definitive radiation were able to undergo salvage treatment, and locoregional and/or distant disease eventually developed in all patients despite salvage surgery.[27] In a University of Florida series of 139 patients with positive nodes treated using radiotherapy alone, 35 developed neck recurrence; salvage was attempted in 9 patients, but successful in only 2.[28]

Current Management Recommendations

In summary, no randomized trials have investigated the management of the neck following concurrent chemoradiation. There appears to be little controversy about simply observing the N1 neck that exhibits a complete response. For the node-positive neck exhibiting less than a complete response, it would be appropriate to proceed with neck dissection. In theabsence of convincing data to the contrary, the patient with an N2 or N3 neck who exhibits a complete response to treatment should be managed with a planned neck dissection.

FIGURE 1

Management of the Posttreatment Neck

The reason for this recommendation becomes clear when one considers that we generally use 20% risk of regional metastases to decide on elective neck dissections in previously untreated patients with clinically N0 necks. The risk of pathologically nodepositive disease in patients with initially bulky neck node metastases who have undergone chemoradiation must be significantly higher than 20%. Even if, for argument's sake, it is lower than a 20% risk, the difficulty in clinically assessing the posttreatment neck further supports the case for neck dissection in this patient population. Taking into account the various controversies surrounding the decision-making process in the management of the posttreatment neck, a recommended pathway for the management of these patients is presented in Figure 1.

If neck dissection is to be includedin a concurrent chemoradiation regimen, when should it occur? Again, no data suggest an optimal time. Nevertheless, surgery should not be undertaken so early as to make dissection difficult due to hypoxemia and excessive intraoperative bleeding. On the other hand, it should not be performed so late that fibrotic changes in the soft tissues of the neck complicate the operative procedure. Taking the above factors into account, a useful guideline for the timing of neck dissection is approximately 6 to 8 weeks following chemoradiation for patients with a complete response and 4 to 6 weeks following chemoradiation for patients with a less than complete response.

The type of neck dissection used to treat chemoradiated patients is also somewhat controversial. Consequent to the realization that in previously treated patients, an aberrant lymphatic pathway may result in unpredictable lymphatic spread, selective neck dissection is less ideal after concurrent chemoradiation. Most authors who advocate posttreatment neck dis-section perform radical or modified radical neck dissection preserving the spinal accessory nerve. Robbins and colleagues, however, have advocated the use of selective neck dissection after targeted intra-arterial chemoradiation, citing a regional control rate of 91% after a median follow-up of 36 months.[29]

Conclusions

The management of the clinically positive neck in patients whose neck nodes exhibit a complete response to chemoradiation therapy remains controversial, especially for high-volume nodal metastases from most sites except the nasopharynx and the tonsil. The role of imaging techniques such as FDG-PET scan in this setting remains to be assessed. Considerable progress needs to be made in developing more reliable methods of detecting residual and/or recurrent disease in the treated neck, and more reliable biologic markers of response to chemoradiation need to be identified. Until our ability to predict and detect recurrence in the treated neck improves, it seems prudent to recommend a planned neck dissection for all patients treated with chemoradiation for high-volume neck metastases.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Taylor SG, Murthy AK, Vannetzel JM, etal: Randomized comparison of neoadjuvantcisplatin and fluorouracil infusion followed byradiation versus concomitant treatment in advancedhead and neck-cancer. J Clin Oncol12:385-395, 1994.

2.

Calais G, Alfonsi M, Bardet E, et al: Randomizedtrial of radiation therapy versus concomitantchemotherapy and radiation therapyfor advanced-stage oropharynx carcinoma. JNatl Cancer Inst 91:2081-2086, 1999.

3.

Adelstein DJ, Li Y, Adams GL, et al: Intergroupphase III comparison of standard radiationtherapy and two schedules of concurrentchemoradiotherapy in patients withunresectable squamous cell head and neck cancer.J Clin Oncol 21:92-98, 2003.

4.

Adelstein DJ, Saxton JP, Lavertu P, etal: A phase III randomized trial comparingconcurrent chemotherapy and radiotherapywith radiotherapy alone in resectable stage IIIand IV squamous cell head and neck cancer:Preliminary results. Head Neck 19:567-575,1997.

5.

Al Sarraf M: Editorial comment: Improvingthe cure rate and overall survival of patientswith nasopharyngeal cancers by improving thesystemic chemotherapy. Head Neck 25:447-450, 2003.

6.

Barkley HT, Fletcher GH, Jessee RH, etal: Managment of cervical lymph node metastasesin squamous cell carcinomas of thetonsillar fossa, base of tongue, supraglottic larynxand hypopharynx. Am J Surg 124:462-467,1972.

7.

Armstrong J, Pfister D, Strong E, et al:The management of the clinically positive neckas part of a larynx preservation approach. Int JRadiat Oncol Biol Phys 26:759-765, 1993.

8.

Wolf GT, Fisher SG: Effectiveness of salvageneck dissection for advanced regionalmetastases when induction chemotherapy andradiation are used for organ preservation.Laryngoscope 102:934-939, 1992.

9.

Weisman RA, Robbins KT: Managementof the neck in patients with head and neck cancertreated by concurrent chemotherapy andradiation. Otolaryngol Clin North Am 3:773,1998.

10.

Narayan K, Crane CH, Kleid S, et al:Planned neck dissection as an adjunct to themanagement of patients with advanced neckdisease treated with definitive radiotherapy: Forsome or for all? Head Neck 21:606-613, 1999.

11.

Parsons JT, Mendenhall WM, StringerSP, et al: Squamous cell carcinoma of theoropharynx: Surgery, radiation therapy or both.Cancer 94:2967-2980, 2002.

12.

Dubray BM, Bataini JP, Bernier J, et al:Is reseeding from the primary a plausible causeof node failure. Int J Radiat Oncol Biol Phys25:9-15, 1993.

13.

McHamm SA, Adelstein DJ, RybickiLA, et al: Who merits a neck dissection afterdefinitive chemoradiotherapy for N2-N3 squamouscell head and neck cancer? Head Neck25:791-798, 2003.

14.

Stenson KM, Haraf DJ, Pelzer H, et al: Therole of cervical lymphadenectomy after aggressiveconcomitant chemoradiotherapy-the feasibility ofselective neck dissection. Arch Otolaryngol HeadNeck Surg 126:950-956, 2000.

15.

Wanebo H, Chougule P, Ready N, et al:Surgical resection is necessary to maximizetumor control in function-preserving, aggressivechemoradiation protocols for advancedsquamous cancer of the head and neck (stageIII and IV). Ann Surg Oncol 8:644-650, 2001.

16.

Lavertu P, Adelstein DJ, Saxton JP, etal: Management of the neck in a randomizedtrial comparing concurrent chemotherapy andradiotherapy with radiotherapy alone in resectablestage III and IV squamous cell head andneck cancer. Head Neck 19:559-566, 1997.

17.

Koch WM, Lee DJ, Eisele DW, et al:Chemoradiotherapy for organ preservation inoral and pharyngeal carcinoma. ArchOtolaryngol Head Neck Surg 121:974-980,1995.

18.

Lavertu P, Bonafede JP, Adelstein DJ, etal: Comparison of surgical complications afterorgan-preservation therapy in patients withstage III or IV squamous cell head and neckcancer. Arch Otolaryngol Head Neck Surg124:401-406, 1998.

19.

Wang SJ, Wang MB, Calcaterra TC:Radiotherapy followed by neck dissection forsmall head and neck cancers with advancedcervical metastases. Ann Otol Rhinol Laryngol108:128-131, 1999.

20.

Dagum P, Pinto HA, Newman JP, et al:Management of the clinically positive neck inorgan preservation for advanced head and neckcancer. Am J Surg 176:448-452, 1998.

21.

Strasser MD, Gleich LL, Miller MA, etal:Management implications of evaluating theN2 and N3 neck after organ preservationtherapy. Laryngoscope 109:1776-1780, 1999.

22.

Newman JP, Terris DJ, Pinto HA, et al:Surgical morbidity of neck dissection afterchemoradiotherapy in advanced head and neckcancer. Ann Otol Rhinol Laryngol 106:117-122,1997.

23.

Wong RJ, Lin DT, Schoder H, et al: Diagnosticand prognostic value of [F-18]fluorodeoxyglucose positron emission tomographyfor recurrent head and neck squamouscell carcinoma. J Clin Oncol 20:4199-4208, 2002.

24.

Schechter NR, Gillenwater AM, ByersRM, et al: Can positron emission tomographyimprove the quality of care for head-and-neckcancer patients? Int J Radiat Oncol Biol Phys51:4-9, 2001.

25.

Greven KM, Williams DW, McGuirt WF,et al: Serial positron emission tomographyscans following radiation therapy of patientswith head and neck cancer. Head Neck 23:942-946, 2001.

26.

Fortin A, Raybaud-Diogene H, Tetu B,et al: Markers of neck failure in oral cavity andoropharyngeal carcinomas treated with radiotherapy.Head Neck 23:87-93, 2001.

27.

Mabanta SR, Mendenhall WM, StringerSP, et al: Salvage treatment for neck recurrenceafter irradiation alone for head and neck squamouscell carcinoma with clinically positiveneck nodes. Head Neck 21:591-594, 1999.

28.

Mendenhall WM, Million RR, CassisiNJ: Squamous-cell carcinoma of the head andneck treated with radiation therapy-the roleof neck dissection for clinically positive necknodes. Int J Radiat Oncol Biol Phys 12:733-740, 1986.

29.

Robbins KT, Wong FSH, Kumar P, et al:Efficacy of targeted chemoradiation andplanned selective neck dissection to controlbulky nodal disease in advanced head and neckcancer. Arch Otolaryngol Head Neck Surg125:670-675, 1999.