- Email: [email protected]
Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes
Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 3, pp. 678 – 683, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter
doi:10.1016/j.ijrobp.2005.08.020
CLINICAL INVESTIGATION
Head and Neck
DETERMINING OPTIMAL CLINICAL TARGET VOLUME MARGINS IN HEAD-AND-NECK CANCER BASED ON MICROSCOPIC EXTRACAPSULAR EXTENSION OF METASTATIC NECK NODES SMITH APISARNTHANARAX, M.D.,* DANIELLE D. ELLIOTT, M.D.,† ADEL K. EL-NAGGAR, M.D., PH.D.,† JOSHUA A. ASPER, P.A.,‡ ANGEL BLANCO, M.D.,‡ K. KIAN ANG, M.D., PH.D.,‡ ADAM S. GARDEN, M.D.,‡ WILLIAM H. MORRISON, M.D.,‡ DAVID ROSENTHAL, M.D.,‡ RANDAL S. WEBER, M.D.,§ AND K. S. CLIFFORD CHAO, M.D.*‡ Departments of *Experimental Radiation Oncology, †Pathology, ‡Radiation Oncology, and §Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: To determine the optimal clinical target volume margins around the gross nodal tumor volume in head-and-neck cancer by assessing microscopic tumor extension beyond cervical lymph node capsules. Methods and Materials: Histologic sections of 96 dissected cervical lymph nodes with extracapsular extension (ECE) from 48 patients with head-and-neck squamous cell carcinoma were examined. The maximum linear distance from the external capsule border to the farthest extent of the tumor or tumoral reaction was measured. The trends of ECE as a function of the distance from the capsule and lymph node size were analyzed. Results: The median diameter of all lymph nodes was 11.0 mm (range: 3.0 –30.0 mm). The mean and median ECE extent was 2.2 mm and 1.6 mm, respectively (range: 0.4 –9.0 mm). The ECE was <5 mm from the capsule in 96% of the nodes. As the distance from the capsule increased, the probability of tumor extension declined. No significant difference between the extent of ECE and lymph node size was observed. Conclusion: For N1 nodes that are at high risk for ECE but not grossly infiltrating musculature, 1 cm clinical target volume margins around the nodal gross tumor volume are recommended to cover microscopic nodal extension in head-and-neck cancer. © 2006 Elsevier Inc. Head and neck, Lymph node, Clinical target volume, Extracapsular extension.
INTRODUCTION Technologic advances in radiation therapy have now made intensity-modulated radiation therapy (IMRT) a feasible option in routine clinical practice. The potential dosimetric superiority of IMRT offers the advantage of better tumor target coverage and critical normal tissue sparing and has generated promising treatment results, particularly in patients with prostate and head-and-neck cancers (1– 6). However, extensive research to optimize treatment planning and target definition is still needed. One of the key elements to the successful implementation of IMRT is the proper delineation of target volumes on planning computed tomography (CT) images. Accurately contouring the gross tumor volume (GTV) and clinical target volume (CTV) in head-and-
neck cancer poses a great challenge for physicians and has been addressed by several groups of investigators (7–10). Currently, no consensus exists regarding the microscopic extent of disease or the CTV margins that should surround gross nodal disease. How far to extend the nodal CTV beyond the GTV is largely empiric and mainly left to the discretion of the physician. The nodal CTV margins around gross disease in patients with head-and-neck cancer can typically range from 5 mm to 2 cm at various institutions. Whether these arbitrary CTV margins are excessive or inadequate remains uncertain. The delineation of nodal CTV in head-and-neck cancer must take into account the potential for extracapsular extension (ECE) in cervical lymph nodes with metastatic disease. This is due to the adverse prognostic impact of ECE
Reprint requests to: K. S. Clifford Chao, M.D., Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel: (713) 563-2300; Fax: (713) 563-2331; E-mail: [email protected] Smith Apisarnthanarax, M.D., is now at the Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Presented at the Forty-Sixth Annual American Society for Therapeutic Radiology and Oncology (ASTRO) Meeting, October 3–7, 2004, Atlanta, GA. Acknowledgments—We thank Yvette Banuelos for her assistance in collecting the slide specimens and Beth L. Notzon for her invaluable editorial review of the manuscript. Received Mar 24, 2005, and in revised form Aug 17, 2005. Accepted for publication Aug 20, 2005. 678
Nodal CTV margins based on pathologic ECE
on recurrence and survival, as shown by several independent studies (11–21). The incidence of local recurrence increases, and the survival rate decreases by greater than 50% when metastatic nodal disease expands beyond the capsule (11, 12, 17, 22, 23). These findings underscore the importance of adequately encompassing all ECE in the nodal CTV. Therefore, it is important to determine the optimal CTV margins for lymph nodes at a high risk for ECE. In this histopathologic study, we examine the extent of microscopic tumor extension outside the nodal capsule to provide insight into the appropriate nodal CTV margins. METHODS AND MATERIALS Specimen selection The head-and-neck database at The University of Texas M. D. Anderson Cancer Center was searched with institutional review board approval for all head-and-neck cancer patients who were status postcervical lymphadenectomy between January 1992 and October 2003. Patients who had received preoperative radiation therapy or who underwent surgery outside our institution were not included in the study. We retrospectively analyzed microscopic ECE in the nodal specimens from 80 patients with nodal disease measuring up to 30 mm in size and with documented pathologic ECE in at least one lymph node. Thirty-two of the 80 patients were excluded from the analysis for the following reasons: (1) Slides were not available for ECE measurement (n ⫽ 21), (2) No evidence of ECE was seen by the study pathologist (D.E.) (n ⫽ 6), or (3) ECE was unmeasurable according to the criteria outlined below (n ⫽ 5).
Patient characteristics Pertinent patient characteristics are summarized in Table 1. The age of the 48 patients whose specimens were evaluable ranged from 35 to 81 years (median, 58 years), and the majority of patients were male (67%). Nearly half of the tumors originated in the oral cavity (48%). According to the American Joint Committee on Cancer 2002 staging guidelines (24), the majority of patients had pathologic N2b (56%) regional nodal disease, and the disease in 96% of these patients was in Stage IV. The greatest percentage (75%) of specimens was obtained during selective neck dissections. A median of two ECE-positive lymph node specimens was examined for each patient (range, 1– 4 specimens). Tumor histology was squamous cell carcinoma in all patients.
Extracapsular extension measurement To avoid interobserver variations, the same pathologist (D.E.) assessed the specimens and identified microscopic evidence of ECE. ECE was defined as extension of the tumor through the lymph node capsule, and this was indicated by the finding of actual tumor cells; an associated desmoplastic stromal response, as previously described (25, 26); or a giant cell reaction to extracellular keratin extending outside the capsule. A micrometer was used to measure the maximum linear distance from the external capsule border to the farthest extent of the tumor or the tumoral reaction, and the measurement was rounded to the nearest tenth of a millimeter. A single investigator (S.A.) performed all measurements. If relevant points of the capsule were obliterated by tumor, the outer limit of the capsule was extrapolated from the nearest intact portion of the capsule, and the ECE was measured from that reference point. It should be noted that in such cases, it is possible
● S. APISARNTHANARAX et al.
679
Table 1. Patient characteristics Characteristic Age (y) Mean ⫾ SD Median Range Gender Male Female Site Oral cavity Oropharynx Hypopharynx Larynx Stage* III IV Tumor stage* T1 T2 T3 T4 Tx Nodal stage* N1 N2a N2b N2c Neck dissection Radical Modified Selective Extracapsular extension ⫹ lymph nodes† Mean and median Range
n (%) 56.3 ⫾ 10.5 58 35–81 32 (66.7) 16 (33.3) 23 (47.9) 6 (12.5) 10 (20.8) 9 (18.8) 2 (4.2) 46 (95.8) 1 (2.1) 6 (12.5) 11 (22.9) 27 (56.3) 3 (6.3) 4 (8.3) 1 (2.1) 27 (56.3) 16 (33.3) 3 (6.3) 9 (18.8) 36 (75.0) 2 1–4
* Pathologic staging according to American Joint Committee on Cancer 2002 staging guidelines (24). † Number per patient.
that measurement of the ECE was underestimated. As noted above, if the entire lymph node or nodal capsule was obliterated by tumor, the specimen was deemed unmeasurable and excluded from the analysis, because of the possibility that these represented extralymphatic soft tissue tumor deposits. The largest axial diameter of each lymph node was also measured. An example of microscopic tumor extension outside the capsule in a metastatic lymph node as measured in the current study is shown in Fig. 1.
Statistical analysis Logarithmic regression analysis was used to determine the trend between ECE frequency and distance from the capsule (27). Spearman’s rank correlation was performed to evaluate the relationship of the extent of ECE with lymph node size. The Student’s t-test was used to compare nodal ECE between different groups of lymph node size (ⱕ10 mm vs. ⬎10 mm) and between oral and nonoral primary tumors. These lymph node size criteria were chosen to link our observations with CT imaging size criteria for pathologic lymph nodes (typically ⬎10 mm). Values with p ⬍ 0.05 were considered statistically significant.
680
I. J. Radiation Oncology
● Biology ● Physics
Volume 64, Number 3, 2006 10 9 8
ECE (mm)
7
Fig. 1. Representative example of extracapsular extension measured outside the nodal capsule of a 2.3-cm metastatic lymph node from a patient with a T4N2c hypopharyngeal primary tumor. (A) Hematoxylin and eosin–stained cross-section (⫻5 magnification) shows a wide view of the entire lymph node section with the capsule outlined in white. (B) Magnified hematoxylin and eosin view (⫻10 magnification) of tumor (T) extension outside the nodal capsule (C). The site where the tumor ruptured the capsule is denoted by an asterisk (*). The extracapsular extension in this specimen measured 2.6 mm from the external capsule border to the farthest extent of the tumor (yellow line).
RESULTS Sample distribution The median axial diameter of the 96 examined nodes was 11.0 mm (range, 3.0 –30.0 mm). The mean and median ECE measurements were 2.2 mm and 1.6 mm, respectively (range, 0.4 –9.0 mm). Histogram distributions of lymph node size (Fig. 2A) and ECE (Fig. 2B) show a relatively normal distribution of nodal size and a positively skewed, leptokurtic distribution of ECE (skewness 1.86, kurtosis 4.82). Extent of ECE The ECE in 92 of the 96 lymph nodes (96%) extended ⬍5 mm from the capsule. The largest percentage of lymph nodes (35%) showed ECE that extended to within 1 to 2 mm outside the capsule. Regression analysis reveals a statistically significant negative correlation between the frequency of ECE and the distance from the capsule (r ⫽ 0.86, p ⬍ 0.01), such that the probability of finding tumor extension outside the capsule declined at greater distances from the capsule (Fig. 2B). In the 4 patients with ECE that extended ⬎5
6 5 4 3 2 1 0 0
5
10
15
20
25
30
35
Lymph Node Size (mm)
Fig. 3. Distribution of extracapsular extension according to lymph node size for all 96 extracapsular extension–positive nodes from 48 head-and-neck cancer patients.
mm outside the capsule, the lymph node was ⬍10 mm in diameter in 2 of them. These two nodes were reexamined, but neither was found to possess unusual pathologic characteristics. Relationship between ECE and nodal size Figure 3 is a scatter plot showing the ECE distribution of all individual lymph nodes examined according to size. Overall, no significant correlation was found between extent of ECE and lymph node size (rs ⫽ 0.13). In particular, mean ECE distances between lymph nodes ⱕ10 mm and ⬎10 mm in diameter did not differ significantly (2.1 mm and 2.2 mm, respectively, p ⫽ 0.72). When the cumulative ECE percentage between ⱕ10 mm and ⬎10 mm nodes was compared, those that were ⬎10 mm in diameter tended to show a greater probability of ECE at a given distance from the capsule. However, this trend disappeared beyond the 4- to 5-mm mark, because of the two small nodes with ECE that extended ⬎5 mm outside the capsule (Fig. 4). When excluding these particular two nodes from data analysis, a greater difference was observed in the mean ECE between
Fig. 2. Frequency distributions of the sample population for (A) lymph node size and (B) extracapsular extension.
Nodal CTV margins based on pathologic ECE 100 90
Cumulative ECE %
80 < 10 mm LNs > 10 mm LNs
70 60 50 40 30 20 10 0 0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
Distance from LN capsule (mm)
Fig. 4. Cumulative extracapsular extension percentage as a function of distance from the lymph node capsule according to lymph node size.
the small- and large-node groups (1.8 vs. 2.2 mm), but this also did not reach statistical significance (p ⫽ 0.07). ECE in oral vs. nonoral tumors The mean and median ECE of metastatic lymph nodes in oral primary tumors were 2.6 mm and 2.4 mm, respectively, and 1.9 mm and 1.5 mm in nonoral primary tumors. Although these differences in extent of ECE did not reach a statistical difference (p ⫽ 0.05), a significant difference existed between the number of ECE-positive lymph nodes per patient: oral 1.7 vs. nonoral 2.3 (p ⫽ 0.03). DISCUSSION This study addresses the need for a general agreement on the definition and extent of CTV margins surrounding nodal GTV in head-and-neck cancer patients. Our results show that the majority (96%) of lymph nodes had ECE that extended ⬍5 mm beyond capsular confinement, and no node showed ECE that extended ⬎10 mm outside the capsule. Although preliminary, our data suggest that margins of 1 cm from the nodal GTV to the CTV would be sufficient to fully cover any subclinical nodal extension for lymph nodes smaller than 3 cm in head-and-neck cancer patients receiving IMRT. In patients receiving conventional radiation therapy, these margins would translate into 1.3 to 1.5 cm from the block edges. Our finding that the probability of a tumor extending outside the nodal capsule decreased as a function of increasing distance from the capsule is consistent with findings from a small number of pathologic studies of primary breast, lung, and vulvar tumors (28 –30). However, because of the limitations of these studies, further detailed pathologic examination was necessary before the clinical application of this information. For example, in the landmark study by Holland et al. (28), the investigators examined mastectomy specimens from breast cancer patients and calculated the distance from the margins of the reference tumor
● S. APISARNTHANARAX et al.
681
to each microscopic focus. For the sake of analysis, however, the authors grouped the lesions that exhibited histologic multifocality according to centimeter intervals, but this does not lend itself to detailed correlation. To our knowledge, the present study is the first to quantify microscopic extension beyond identifiable nodal GTV margins and to determine specific trends with regard to ECE as a function of distance. Several investigators have previously reported that the probability of ECE involvement in metastatic neck lymph nodes is a monotonic function of increasing lymph node size (11, 13–15, 31). Table 2 summarizes the incidence of ECE noted in various studies of lymph nodes of varying sizes with metastatic disease. The tumor was reported to have broken through the capsule of 17% to 43% of nodes as small as 1 cm. This percentage went as high as 65% for metastatic nodes that exceeded 3 cm in diameter. It is plausible to postulate that ECE in larger lymph nodes may have a greater propensity to spread farther from the capsule than in smaller lymph nodes. However, we found no correlation between the size of the cervical nodes and the magnitude of ECE. In fact, some of the smallest nodes examined in our study had the greatest microscopic extent of ECE. Therefore, although it appears from the aforementioned studies that tumors may more frequently spread beyond the capsule of larger lymph nodes, our data suggest they do not necessarily extend farther from the capsule once they rupture the capsule. Our results are consistent with similar studies evaluating microscopic disease extent in primary breast, lung, and vulvar tumors (28 –30). Holland et al. evaluated microscopic extent of invasive ductal carcinoma. In patients with T1–T2 disease, 43% of specimens contained microscopic disease beyond the reference tumor (28). However, there was no correlation between size of the gross tumor and distance of microscopic disease from the gross tumor. Evaluating CTV definitions for lung cancers, Giraud et al. similarly could not find a correlation between tumor size and microscopic extension beyond the tumor (29). The observation that the extent of ECE is not dependent on lymph node size may imply that it is related to the biologic nature and aggressiveness of the metastatic disease. Future studies incorporating bioassays to assess invasive propensity are needed to address these issues. It should be noted, however, that the majority of lymph Table 2. Incidence of extracapsular extension from metastatic neck nodes by size Node size (cm) Study (Ref.)
⬍1
1–3
⬎3
Johnson et al., 1981 (11) Snow et al., 1982 (31) Snyderman et al., 1985 (13) Carter et al., 1987 (14) Hirabayashi et al., 1991 (15)
– 22 – 17 43
65 52 38 83 –
75 74 67 95 81
682
I. J. Radiation Oncology
● Biology ● Physics
nodes examined in the current study were relatively small. Only eight lymph nodes measured more than 2 cm in diameter, and the largest node measured 3.0 cm. This can be attributed to the current practice patterns at our institution, where most patients with oropharyngeal cancer or bulky nodal disease typically receive nonsurgical treatment. It may therefore be possible that the recommended 1 cm CTV margins are too constrictive for patients with larger or matted lymph nodes, particularly ones that infiltrate the musculature. In the case of lymph nodes with gross muscular involvement, we recommend using more generous CTV margins around the nodal GTV. One limitation in our study is that the slides of lymph node specimens that were measured were only representative sections of the bisected node and do not fully illustrate tumor extension outside the capsule in three dimensions. Thus, some areas of tumor could have been missed, and some ECE measurements could be slightly underestimated. In addition, the effect of tissue shrinkage during fixation could not be addressed retrospectively. For these reasons, we are planning to obtain more comprehensive pathologic data in future prospective studies of whole-mount sections of lymph nodes in their entirety to address the magnitude of tissue shrinkage in both small and large nodes. We also acknowledge that observer variation may have potentially influenced the recommendations; however, the shallow correlation in our analysis would suggest that the recommendation of a 1-cm margin around N1 disease is still likely to be valid. To translate the pathologic findings from this study into the clinical setting requires the correlation of the pathologic features with the imaging findings. Others have examined the relationship between the gross tumor size measured on radiologic images and that measured in pathologic studies (29, 30, 32–36). Imaging-histopathologic correlations of laryngeal tumors, for example, generally revealed good correlation of gross tumor extent between whole-mount specimens and CT images, although overestimation and underestimation of tumor extent were found in some cases (32). Preoperative CT scans were available for 10 patients in the study; the other patients were referred mainly from outside hospitals, and thus we did not have preoperative CT films for them. When node sizes were compared between the radiologic images and the pathologic slides in these 10 patients, we noted that some lymph nodes measured larger and others measured smaller on CT images than in the slides (data not shown). This is perhaps due to crude coregistration of the specific lymph nodes on CT images with the pathologic specimens as a result of the retrospective nature of this study or unac-
Volume 64, Number 3, 2006
Fig. 5. Correlation of pathology and axial computed tomography (CT) imaging findings for a level III/IV 2.0-cm left neck node (white outline) from a patient with a T3N2a hypopharyngeal tumor. Hematoxylin and eosin–stained specimen (⫻10 magnification; insert to the right of A) shows microscopic extracapsular extension that extends 3 mm in its farthest extent outside the lymph node capsule (yellow line). LN ⫽ lymph node, C ⫽ capsule, T ⫽ microscopic tumor extension outside capsule. (B) Nodal gross tumor volume outlined and shaded in red on the planning CT. (C) Clinical target volume margins (outlined in green) of 1 cm around the CT-defined nodal gross tumor volume would be sufficient to encompass the 3-mm extracapsular extension in this lymph node.
counted shrinkage of the tissue specimens. In future prospective studies, we plan to incorporate anatomic (computed tomography) and functional (positron emission tomography) imaging to assess imaging-pathologic correlation by performing node-to-node coregistration. Figure 5 illustrates an example of how such imaging-pathologic correlations could be applied clinically for the purpose of CTV margin delineation in IMRT treatment planning. CONCLUSION We have observed that the degree of ECE does not appear to be related to lymph node size but may instead be governed by the biologic nature of the tumor. Based on pathologic ECE investigation, we recommend using 1-cm CTV margins around the nodal GTV in patients with pathologic lymph nodes ⱕ3 cm in diameter (N1 disease) that do not grossly infiltrate the musculature but are at high risk for ECE. Future prospective studies will focus on imaging-pathologic correlation and include specimens of larger neck nodes.
REFERENCES 1. Chao KS, Ozyigit G, Tran BN, et al. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003;55:312–321. 2. Chao KS, Ozyigit G, Blanco AI, et al. Intensity-modulated radiation therapy for oropharyngeal carcinoma: Impact of tumor volume. Int J Radiat Oncol Biol Phys 2004;59:43–50. 3. Dawson LA, Anzai Y, Marsh L, et al. Patterns of local-
regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2000;46:1117–1126. 4. Eisbruch A, Ship JA, Dawson LA, et al. Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg 2003;27:832– 837.
Nodal CTV margins based on pathologic ECE
5. Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001; 166:876 – 881. 6. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111–1116. 7. Chao KS, Wippold FJ, Ozyigit G, et al. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53: 1174 –1184. 8. Levendag P, Braaksma M, Coche E, et al. Rotterdam and Brussels CT-based neck nodal delineation compared with the surgical levels as defined by the American Academy of Otolaryngology-Head and Neck Surgery. Int J Radiat Oncol Biol Phys 2004;58:113–123. 9. Gregoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol 2003;69:227–236. 10. Eisbruch A, Foote RL, O’Sullivan B, et al. Intensity-modulated radiation therapy for head and neck cancer: Emphasis on the selection and delineation of the targets. Semin Radiat Oncol 2002;12:238 –249. 11. Johnson JT, Barnes EL, Myers EN, et al. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol 1981;107:725–729. 12. Johnson JT, Myers EN, Bedetti CD, et al. Cervical lymph node metastases. Incidence and implications of extracapsular carcinoma. Arch Otolaryngol 1985;111:534 –537. 13. Snyderman NL, Johnson JT, Schramm VL, Jr., et al. Extracapsular spread of carcinoma in cervical lymph nodes. Impact upon survival in patients with carcinoma of the supraglottic larynx. Cancer 1985;56:1597–1599. 14. Carter RL, Bliss JM, Soo KC, et al. Radical neck dissections for squamous carcinomas: Pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Radiat Oncol Biol Phys 1987;13:825– 832. 15. Hirabayashi H, Koshii K, Uno K, et al. Extracapsular spread of squamous cell carcinoma in neck lymph nodes: Prognostic factor of laryngeal cancer. Laryngoscope 1991;101:502–506. 16. Huang DT, Johnson CR, Schmidt-Ullrich R, et al. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: A comparative study. Int J Radiat Oncol Biol Phys 1992;23: 737–742. 17. Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: A prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck 1998;20:16 –21. 18. Myers JN, Greenberg JS, Mo V, et al. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer 2001;92:3030 – 3036. 19. Woolgar JA, Rogers S, West CR, et al. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 1999;35:257–265.
● S. APISARNTHANARAX et al.
683
20. Woolgar JA, Rogers SN, Lowe D, et al. Cervical lymph node metastasis in oral cancer: The importance of even microscopic extracapsular spread. Oral Oncol 2003;39:130 –137. 21. Puri SK, Fan CY, Hanna E. Significance of extracapsular lymph node metastases in patients with head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg 2003;11:119 –123. 22. Bennett SH, Futrell JW, Roth JA, et al. Prognostic significance of histologic host response in cancer of the larynx or hypopharynx. Cancer 1971;28:1255–1265. 23. Noone RB, Bonner H, Jr., Raymond S, et al. Lymph node metastases in oral carcinoma. A correlation of histopathology with survival. Plast Reconstr Surg 1974;53:158 –166. 24. Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2002. 25. Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: The prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck 2002;24:258 –261. 26. Ferlito A, Rinaldo A, Devaney KO, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol 2002;38:747–751. 27. Dawson BK. Basic and clinical biostatistics. 3rd ed. New York: McGraw-Hill/Appleton & Lange; 2004. 28. Holland R, Veling SH, Mravunac M, et al. Histologic multifocality of Tis, T1–2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56:979 – 990. 29. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 2000;48:1015–1024. 30. Hoffman MS, Gunesakaran S, Arango H, et al. Lateral microscopic extension of squamous cell carcinoma of the vulva. Gynecol Oncol 1999;73:72–75. 31. Snow GB, Annyas AA, van Slooten EA, et al. Prognostic factors of neck node metastasis. Clin Otolaryngol 1982;7: 185–192. 32. Archer CR, Yeager VL. Computed tomography of laryngeal cancer with histopathological correlation. Laryngoscope 1982; 92:1173–1180. 33. Mafee MF, Schild JA, Valvassori GE, et al. Computed tomography of the larynx: Correlation with anatomic and pathologic studies in cases of laryngeal carcinoma. Radiology 1983; 147:123–128. 34. Schild JA, Valvassori GE, Mafee MF, et al. Laryngeal malignancies and computerized tomography. A correlation of tomographic and histopathologic findings. Ann Otol Rhinol Laryngol 1982;91:571–575. 35. Silverman PM, Bossen EH, Fisher SR, et al. Carcinoma of the larynx and hypopharynx: Computed tomographic-histopathologic correlations. Radiology 1984;151:697–702. 36. Teh BS, Bastasch MD, Wheeler TM, et al. IMRT for prostate cancer: Defining target volume based on correlated pathologic volume of disease. Int J Radiat Oncol Biol Phys 2003;56:184 – 191.
doi:10.1016/j.ijrobp.2005.08.020
CLINICAL INVESTIGATION
Head and Neck
DETERMINING OPTIMAL CLINICAL TARGET VOLUME MARGINS IN HEAD-AND-NECK CANCER BASED ON MICROSCOPIC EXTRACAPSULAR EXTENSION OF METASTATIC NECK NODES SMITH APISARNTHANARAX, M.D.,* DANIELLE D. ELLIOTT, M.D.,† ADEL K. EL-NAGGAR, M.D., PH.D.,† JOSHUA A. ASPER, P.A.,‡ ANGEL BLANCO, M.D.,‡ K. KIAN ANG, M.D., PH.D.,‡ ADAM S. GARDEN, M.D.,‡ WILLIAM H. MORRISON, M.D.,‡ DAVID ROSENTHAL, M.D.,‡ RANDAL S. WEBER, M.D.,§ AND K. S. CLIFFORD CHAO, M.D.*‡ Departments of *Experimental Radiation Oncology, †Pathology, ‡Radiation Oncology, and §Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: To determine the optimal clinical target volume margins around the gross nodal tumor volume in head-and-neck cancer by assessing microscopic tumor extension beyond cervical lymph node capsules. Methods and Materials: Histologic sections of 96 dissected cervical lymph nodes with extracapsular extension (ECE) from 48 patients with head-and-neck squamous cell carcinoma were examined. The maximum linear distance from the external capsule border to the farthest extent of the tumor or tumoral reaction was measured. The trends of ECE as a function of the distance from the capsule and lymph node size were analyzed. Results: The median diameter of all lymph nodes was 11.0 mm (range: 3.0 –30.0 mm). The mean and median ECE extent was 2.2 mm and 1.6 mm, respectively (range: 0.4 –9.0 mm). The ECE was <5 mm from the capsule in 96% of the nodes. As the distance from the capsule increased, the probability of tumor extension declined. No significant difference between the extent of ECE and lymph node size was observed. Conclusion: For N1 nodes that are at high risk for ECE but not grossly infiltrating musculature, 1 cm clinical target volume margins around the nodal gross tumor volume are recommended to cover microscopic nodal extension in head-and-neck cancer. © 2006 Elsevier Inc. Head and neck, Lymph node, Clinical target volume, Extracapsular extension.
INTRODUCTION Technologic advances in radiation therapy have now made intensity-modulated radiation therapy (IMRT) a feasible option in routine clinical practice. The potential dosimetric superiority of IMRT offers the advantage of better tumor target coverage and critical normal tissue sparing and has generated promising treatment results, particularly in patients with prostate and head-and-neck cancers (1– 6). However, extensive research to optimize treatment planning and target definition is still needed. One of the key elements to the successful implementation of IMRT is the proper delineation of target volumes on planning computed tomography (CT) images. Accurately contouring the gross tumor volume (GTV) and clinical target volume (CTV) in head-and-
neck cancer poses a great challenge for physicians and has been addressed by several groups of investigators (7–10). Currently, no consensus exists regarding the microscopic extent of disease or the CTV margins that should surround gross nodal disease. How far to extend the nodal CTV beyond the GTV is largely empiric and mainly left to the discretion of the physician. The nodal CTV margins around gross disease in patients with head-and-neck cancer can typically range from 5 mm to 2 cm at various institutions. Whether these arbitrary CTV margins are excessive or inadequate remains uncertain. The delineation of nodal CTV in head-and-neck cancer must take into account the potential for extracapsular extension (ECE) in cervical lymph nodes with metastatic disease. This is due to the adverse prognostic impact of ECE
Reprint requests to: K. S. Clifford Chao, M.D., Department of Radiation Oncology, Unit 97, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel: (713) 563-2300; Fax: (713) 563-2331; E-mail: [email protected] Smith Apisarnthanarax, M.D., is now at the Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Presented at the Forty-Sixth Annual American Society for Therapeutic Radiology and Oncology (ASTRO) Meeting, October 3–7, 2004, Atlanta, GA. Acknowledgments—We thank Yvette Banuelos for her assistance in collecting the slide specimens and Beth L. Notzon for her invaluable editorial review of the manuscript. Received Mar 24, 2005, and in revised form Aug 17, 2005. Accepted for publication Aug 20, 2005. 678
Nodal CTV margins based on pathologic ECE
on recurrence and survival, as shown by several independent studies (11–21). The incidence of local recurrence increases, and the survival rate decreases by greater than 50% when metastatic nodal disease expands beyond the capsule (11, 12, 17, 22, 23). These findings underscore the importance of adequately encompassing all ECE in the nodal CTV. Therefore, it is important to determine the optimal CTV margins for lymph nodes at a high risk for ECE. In this histopathologic study, we examine the extent of microscopic tumor extension outside the nodal capsule to provide insight into the appropriate nodal CTV margins. METHODS AND MATERIALS Specimen selection The head-and-neck database at The University of Texas M. D. Anderson Cancer Center was searched with institutional review board approval for all head-and-neck cancer patients who were status postcervical lymphadenectomy between January 1992 and October 2003. Patients who had received preoperative radiation therapy or who underwent surgery outside our institution were not included in the study. We retrospectively analyzed microscopic ECE in the nodal specimens from 80 patients with nodal disease measuring up to 30 mm in size and with documented pathologic ECE in at least one lymph node. Thirty-two of the 80 patients were excluded from the analysis for the following reasons: (1) Slides were not available for ECE measurement (n ⫽ 21), (2) No evidence of ECE was seen by the study pathologist (D.E.) (n ⫽ 6), or (3) ECE was unmeasurable according to the criteria outlined below (n ⫽ 5).
Patient characteristics Pertinent patient characteristics are summarized in Table 1. The age of the 48 patients whose specimens were evaluable ranged from 35 to 81 years (median, 58 years), and the majority of patients were male (67%). Nearly half of the tumors originated in the oral cavity (48%). According to the American Joint Committee on Cancer 2002 staging guidelines (24), the majority of patients had pathologic N2b (56%) regional nodal disease, and the disease in 96% of these patients was in Stage IV. The greatest percentage (75%) of specimens was obtained during selective neck dissections. A median of two ECE-positive lymph node specimens was examined for each patient (range, 1– 4 specimens). Tumor histology was squamous cell carcinoma in all patients.
Extracapsular extension measurement To avoid interobserver variations, the same pathologist (D.E.) assessed the specimens and identified microscopic evidence of ECE. ECE was defined as extension of the tumor through the lymph node capsule, and this was indicated by the finding of actual tumor cells; an associated desmoplastic stromal response, as previously described (25, 26); or a giant cell reaction to extracellular keratin extending outside the capsule. A micrometer was used to measure the maximum linear distance from the external capsule border to the farthest extent of the tumor or the tumoral reaction, and the measurement was rounded to the nearest tenth of a millimeter. A single investigator (S.A.) performed all measurements. If relevant points of the capsule were obliterated by tumor, the outer limit of the capsule was extrapolated from the nearest intact portion of the capsule, and the ECE was measured from that reference point. It should be noted that in such cases, it is possible
● S. APISARNTHANARAX et al.
679
Table 1. Patient characteristics Characteristic Age (y) Mean ⫾ SD Median Range Gender Male Female Site Oral cavity Oropharynx Hypopharynx Larynx Stage* III IV Tumor stage* T1 T2 T3 T4 Tx Nodal stage* N1 N2a N2b N2c Neck dissection Radical Modified Selective Extracapsular extension ⫹ lymph nodes† Mean and median Range
n (%) 56.3 ⫾ 10.5 58 35–81 32 (66.7) 16 (33.3) 23 (47.9) 6 (12.5) 10 (20.8) 9 (18.8) 2 (4.2) 46 (95.8) 1 (2.1) 6 (12.5) 11 (22.9) 27 (56.3) 3 (6.3) 4 (8.3) 1 (2.1) 27 (56.3) 16 (33.3) 3 (6.3) 9 (18.8) 36 (75.0) 2 1–4
* Pathologic staging according to American Joint Committee on Cancer 2002 staging guidelines (24). † Number per patient.
that measurement of the ECE was underestimated. As noted above, if the entire lymph node or nodal capsule was obliterated by tumor, the specimen was deemed unmeasurable and excluded from the analysis, because of the possibility that these represented extralymphatic soft tissue tumor deposits. The largest axial diameter of each lymph node was also measured. An example of microscopic tumor extension outside the capsule in a metastatic lymph node as measured in the current study is shown in Fig. 1.
Statistical analysis Logarithmic regression analysis was used to determine the trend between ECE frequency and distance from the capsule (27). Spearman’s rank correlation was performed to evaluate the relationship of the extent of ECE with lymph node size. The Student’s t-test was used to compare nodal ECE between different groups of lymph node size (ⱕ10 mm vs. ⬎10 mm) and between oral and nonoral primary tumors. These lymph node size criteria were chosen to link our observations with CT imaging size criteria for pathologic lymph nodes (typically ⬎10 mm). Values with p ⬍ 0.05 were considered statistically significant.
680
I. J. Radiation Oncology
● Biology ● Physics
Volume 64, Number 3, 2006 10 9 8
ECE (mm)
7
Fig. 1. Representative example of extracapsular extension measured outside the nodal capsule of a 2.3-cm metastatic lymph node from a patient with a T4N2c hypopharyngeal primary tumor. (A) Hematoxylin and eosin–stained cross-section (⫻5 magnification) shows a wide view of the entire lymph node section with the capsule outlined in white. (B) Magnified hematoxylin and eosin view (⫻10 magnification) of tumor (T) extension outside the nodal capsule (C). The site where the tumor ruptured the capsule is denoted by an asterisk (*). The extracapsular extension in this specimen measured 2.6 mm from the external capsule border to the farthest extent of the tumor (yellow line).
RESULTS Sample distribution The median axial diameter of the 96 examined nodes was 11.0 mm (range, 3.0 –30.0 mm). The mean and median ECE measurements were 2.2 mm and 1.6 mm, respectively (range, 0.4 –9.0 mm). Histogram distributions of lymph node size (Fig. 2A) and ECE (Fig. 2B) show a relatively normal distribution of nodal size and a positively skewed, leptokurtic distribution of ECE (skewness 1.86, kurtosis 4.82). Extent of ECE The ECE in 92 of the 96 lymph nodes (96%) extended ⬍5 mm from the capsule. The largest percentage of lymph nodes (35%) showed ECE that extended to within 1 to 2 mm outside the capsule. Regression analysis reveals a statistically significant negative correlation between the frequency of ECE and the distance from the capsule (r ⫽ 0.86, p ⬍ 0.01), such that the probability of finding tumor extension outside the capsule declined at greater distances from the capsule (Fig. 2B). In the 4 patients with ECE that extended ⬎5
6 5 4 3 2 1 0 0
5
10
15
20
25
30
35
Lymph Node Size (mm)
Fig. 3. Distribution of extracapsular extension according to lymph node size for all 96 extracapsular extension–positive nodes from 48 head-and-neck cancer patients.
mm outside the capsule, the lymph node was ⬍10 mm in diameter in 2 of them. These two nodes were reexamined, but neither was found to possess unusual pathologic characteristics. Relationship between ECE and nodal size Figure 3 is a scatter plot showing the ECE distribution of all individual lymph nodes examined according to size. Overall, no significant correlation was found between extent of ECE and lymph node size (rs ⫽ 0.13). In particular, mean ECE distances between lymph nodes ⱕ10 mm and ⬎10 mm in diameter did not differ significantly (2.1 mm and 2.2 mm, respectively, p ⫽ 0.72). When the cumulative ECE percentage between ⱕ10 mm and ⬎10 mm nodes was compared, those that were ⬎10 mm in diameter tended to show a greater probability of ECE at a given distance from the capsule. However, this trend disappeared beyond the 4- to 5-mm mark, because of the two small nodes with ECE that extended ⬎5 mm outside the capsule (Fig. 4). When excluding these particular two nodes from data analysis, a greater difference was observed in the mean ECE between
Fig. 2. Frequency distributions of the sample population for (A) lymph node size and (B) extracapsular extension.
Nodal CTV margins based on pathologic ECE 100 90
Cumulative ECE %
80 < 10 mm LNs > 10 mm LNs
70 60 50 40 30 20 10 0 0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
Distance from LN capsule (mm)
Fig. 4. Cumulative extracapsular extension percentage as a function of distance from the lymph node capsule according to lymph node size.
the small- and large-node groups (1.8 vs. 2.2 mm), but this also did not reach statistical significance (p ⫽ 0.07). ECE in oral vs. nonoral tumors The mean and median ECE of metastatic lymph nodes in oral primary tumors were 2.6 mm and 2.4 mm, respectively, and 1.9 mm and 1.5 mm in nonoral primary tumors. Although these differences in extent of ECE did not reach a statistical difference (p ⫽ 0.05), a significant difference existed between the number of ECE-positive lymph nodes per patient: oral 1.7 vs. nonoral 2.3 (p ⫽ 0.03). DISCUSSION This study addresses the need for a general agreement on the definition and extent of CTV margins surrounding nodal GTV in head-and-neck cancer patients. Our results show that the majority (96%) of lymph nodes had ECE that extended ⬍5 mm beyond capsular confinement, and no node showed ECE that extended ⬎10 mm outside the capsule. Although preliminary, our data suggest that margins of 1 cm from the nodal GTV to the CTV would be sufficient to fully cover any subclinical nodal extension for lymph nodes smaller than 3 cm in head-and-neck cancer patients receiving IMRT. In patients receiving conventional radiation therapy, these margins would translate into 1.3 to 1.5 cm from the block edges. Our finding that the probability of a tumor extending outside the nodal capsule decreased as a function of increasing distance from the capsule is consistent with findings from a small number of pathologic studies of primary breast, lung, and vulvar tumors (28 –30). However, because of the limitations of these studies, further detailed pathologic examination was necessary before the clinical application of this information. For example, in the landmark study by Holland et al. (28), the investigators examined mastectomy specimens from breast cancer patients and calculated the distance from the margins of the reference tumor
● S. APISARNTHANARAX et al.
681
to each microscopic focus. For the sake of analysis, however, the authors grouped the lesions that exhibited histologic multifocality according to centimeter intervals, but this does not lend itself to detailed correlation. To our knowledge, the present study is the first to quantify microscopic extension beyond identifiable nodal GTV margins and to determine specific trends with regard to ECE as a function of distance. Several investigators have previously reported that the probability of ECE involvement in metastatic neck lymph nodes is a monotonic function of increasing lymph node size (11, 13–15, 31). Table 2 summarizes the incidence of ECE noted in various studies of lymph nodes of varying sizes with metastatic disease. The tumor was reported to have broken through the capsule of 17% to 43% of nodes as small as 1 cm. This percentage went as high as 65% for metastatic nodes that exceeded 3 cm in diameter. It is plausible to postulate that ECE in larger lymph nodes may have a greater propensity to spread farther from the capsule than in smaller lymph nodes. However, we found no correlation between the size of the cervical nodes and the magnitude of ECE. In fact, some of the smallest nodes examined in our study had the greatest microscopic extent of ECE. Therefore, although it appears from the aforementioned studies that tumors may more frequently spread beyond the capsule of larger lymph nodes, our data suggest they do not necessarily extend farther from the capsule once they rupture the capsule. Our results are consistent with similar studies evaluating microscopic disease extent in primary breast, lung, and vulvar tumors (28 –30). Holland et al. evaluated microscopic extent of invasive ductal carcinoma. In patients with T1–T2 disease, 43% of specimens contained microscopic disease beyond the reference tumor (28). However, there was no correlation between size of the gross tumor and distance of microscopic disease from the gross tumor. Evaluating CTV definitions for lung cancers, Giraud et al. similarly could not find a correlation between tumor size and microscopic extension beyond the tumor (29). The observation that the extent of ECE is not dependent on lymph node size may imply that it is related to the biologic nature and aggressiveness of the metastatic disease. Future studies incorporating bioassays to assess invasive propensity are needed to address these issues. It should be noted, however, that the majority of lymph Table 2. Incidence of extracapsular extension from metastatic neck nodes by size Node size (cm) Study (Ref.)
⬍1
1–3
⬎3
Johnson et al., 1981 (11) Snow et al., 1982 (31) Snyderman et al., 1985 (13) Carter et al., 1987 (14) Hirabayashi et al., 1991 (15)
– 22 – 17 43
65 52 38 83 –
75 74 67 95 81
682
I. J. Radiation Oncology
● Biology ● Physics
nodes examined in the current study were relatively small. Only eight lymph nodes measured more than 2 cm in diameter, and the largest node measured 3.0 cm. This can be attributed to the current practice patterns at our institution, where most patients with oropharyngeal cancer or bulky nodal disease typically receive nonsurgical treatment. It may therefore be possible that the recommended 1 cm CTV margins are too constrictive for patients with larger or matted lymph nodes, particularly ones that infiltrate the musculature. In the case of lymph nodes with gross muscular involvement, we recommend using more generous CTV margins around the nodal GTV. One limitation in our study is that the slides of lymph node specimens that were measured were only representative sections of the bisected node and do not fully illustrate tumor extension outside the capsule in three dimensions. Thus, some areas of tumor could have been missed, and some ECE measurements could be slightly underestimated. In addition, the effect of tissue shrinkage during fixation could not be addressed retrospectively. For these reasons, we are planning to obtain more comprehensive pathologic data in future prospective studies of whole-mount sections of lymph nodes in their entirety to address the magnitude of tissue shrinkage in both small and large nodes. We also acknowledge that observer variation may have potentially influenced the recommendations; however, the shallow correlation in our analysis would suggest that the recommendation of a 1-cm margin around N1 disease is still likely to be valid. To translate the pathologic findings from this study into the clinical setting requires the correlation of the pathologic features with the imaging findings. Others have examined the relationship between the gross tumor size measured on radiologic images and that measured in pathologic studies (29, 30, 32–36). Imaging-histopathologic correlations of laryngeal tumors, for example, generally revealed good correlation of gross tumor extent between whole-mount specimens and CT images, although overestimation and underestimation of tumor extent were found in some cases (32). Preoperative CT scans were available for 10 patients in the study; the other patients were referred mainly from outside hospitals, and thus we did not have preoperative CT films for them. When node sizes were compared between the radiologic images and the pathologic slides in these 10 patients, we noted that some lymph nodes measured larger and others measured smaller on CT images than in the slides (data not shown). This is perhaps due to crude coregistration of the specific lymph nodes on CT images with the pathologic specimens as a result of the retrospective nature of this study or unac-
Volume 64, Number 3, 2006
Fig. 5. Correlation of pathology and axial computed tomography (CT) imaging findings for a level III/IV 2.0-cm left neck node (white outline) from a patient with a T3N2a hypopharyngeal tumor. Hematoxylin and eosin–stained specimen (⫻10 magnification; insert to the right of A) shows microscopic extracapsular extension that extends 3 mm in its farthest extent outside the lymph node capsule (yellow line). LN ⫽ lymph node, C ⫽ capsule, T ⫽ microscopic tumor extension outside capsule. (B) Nodal gross tumor volume outlined and shaded in red on the planning CT. (C) Clinical target volume margins (outlined in green) of 1 cm around the CT-defined nodal gross tumor volume would be sufficient to encompass the 3-mm extracapsular extension in this lymph node.
counted shrinkage of the tissue specimens. In future prospective studies, we plan to incorporate anatomic (computed tomography) and functional (positron emission tomography) imaging to assess imaging-pathologic correlation by performing node-to-node coregistration. Figure 5 illustrates an example of how such imaging-pathologic correlations could be applied clinically for the purpose of CTV margin delineation in IMRT treatment planning. CONCLUSION We have observed that the degree of ECE does not appear to be related to lymph node size but may instead be governed by the biologic nature of the tumor. Based on pathologic ECE investigation, we recommend using 1-cm CTV margins around the nodal GTV in patients with pathologic lymph nodes ⱕ3 cm in diameter (N1 disease) that do not grossly infiltrate the musculature but are at high risk for ECE. Future prospective studies will focus on imaging-pathologic correlation and include specimens of larger neck nodes.
REFERENCES 1. Chao KS, Ozyigit G, Tran BN, et al. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003;55:312–321. 2. Chao KS, Ozyigit G, Blanco AI, et al. Intensity-modulated radiation therapy for oropharyngeal carcinoma: Impact of tumor volume. Int J Radiat Oncol Biol Phys 2004;59:43–50. 3. Dawson LA, Anzai Y, Marsh L, et al. Patterns of local-
regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2000;46:1117–1126. 4. Eisbruch A, Ship JA, Dawson LA, et al. Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg 2003;27:832– 837.
Nodal CTV margins based on pathologic ECE
5. Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001; 166:876 – 881. 6. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111–1116. 7. Chao KS, Wippold FJ, Ozyigit G, et al. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53: 1174 –1184. 8. Levendag P, Braaksma M, Coche E, et al. Rotterdam and Brussels CT-based neck nodal delineation compared with the surgical levels as defined by the American Academy of Otolaryngology-Head and Neck Surgery. Int J Radiat Oncol Biol Phys 2004;58:113–123. 9. Gregoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol 2003;69:227–236. 10. Eisbruch A, Foote RL, O’Sullivan B, et al. Intensity-modulated radiation therapy for head and neck cancer: Emphasis on the selection and delineation of the targets. Semin Radiat Oncol 2002;12:238 –249. 11. Johnson JT, Barnes EL, Myers EN, et al. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol 1981;107:725–729. 12. Johnson JT, Myers EN, Bedetti CD, et al. Cervical lymph node metastases. Incidence and implications of extracapsular carcinoma. Arch Otolaryngol 1985;111:534 –537. 13. Snyderman NL, Johnson JT, Schramm VL, Jr., et al. Extracapsular spread of carcinoma in cervical lymph nodes. Impact upon survival in patients with carcinoma of the supraglottic larynx. Cancer 1985;56:1597–1599. 14. Carter RL, Bliss JM, Soo KC, et al. Radical neck dissections for squamous carcinomas: Pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Radiat Oncol Biol Phys 1987;13:825– 832. 15. Hirabayashi H, Koshii K, Uno K, et al. Extracapsular spread of squamous cell carcinoma in neck lymph nodes: Prognostic factor of laryngeal cancer. Laryngoscope 1991;101:502–506. 16. Huang DT, Johnson CR, Schmidt-Ullrich R, et al. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: A comparative study. Int J Radiat Oncol Biol Phys 1992;23: 737–742. 17. Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: A prospective study of 170 cases of carcinoma of the larynx and hypopharynx. Head Neck 1998;20:16 –21. 18. Myers JN, Greenberg JS, Mo V, et al. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer 2001;92:3030 – 3036. 19. Woolgar JA, Rogers S, West CR, et al. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 1999;35:257–265.
● S. APISARNTHANARAX et al.
683
20. Woolgar JA, Rogers SN, Lowe D, et al. Cervical lymph node metastasis in oral cancer: The importance of even microscopic extracapsular spread. Oral Oncol 2003;39:130 –137. 21. Puri SK, Fan CY, Hanna E. Significance of extracapsular lymph node metastases in patients with head and neck squamous cell carcinoma. Curr Opin Otolaryngol Head Neck Surg 2003;11:119 –123. 22. Bennett SH, Futrell JW, Roth JA, et al. Prognostic significance of histologic host response in cancer of the larynx or hypopharynx. Cancer 1971;28:1255–1265. 23. Noone RB, Bonner H, Jr., Raymond S, et al. Lymph node metastases in oral carcinoma. A correlation of histopathology with survival. Plast Reconstr Surg 1974;53:158 –166. 24. Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2002. 25. Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: The prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck 2002;24:258 –261. 26. Ferlito A, Rinaldo A, Devaney KO, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol 2002;38:747–751. 27. Dawson BK. Basic and clinical biostatistics. 3rd ed. New York: McGraw-Hill/Appleton & Lange; 2004. 28. Holland R, Veling SH, Mravunac M, et al. Histologic multifocality of Tis, T1–2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56:979 – 990. 29. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 2000;48:1015–1024. 30. Hoffman MS, Gunesakaran S, Arango H, et al. Lateral microscopic extension of squamous cell carcinoma of the vulva. Gynecol Oncol 1999;73:72–75. 31. Snow GB, Annyas AA, van Slooten EA, et al. Prognostic factors of neck node metastasis. Clin Otolaryngol 1982;7: 185–192. 32. Archer CR, Yeager VL. Computed tomography of laryngeal cancer with histopathological correlation. Laryngoscope 1982; 92:1173–1180. 33. Mafee MF, Schild JA, Valvassori GE, et al. Computed tomography of the larynx: Correlation with anatomic and pathologic studies in cases of laryngeal carcinoma. Radiology 1983; 147:123–128. 34. Schild JA, Valvassori GE, Mafee MF, et al. Laryngeal malignancies and computerized tomography. A correlation of tomographic and histopathologic findings. Ann Otol Rhinol Laryngol 1982;91:571–575. 35. Silverman PM, Bossen EH, Fisher SR, et al. Carcinoma of the larynx and hypopharynx: Computed tomographic-histopathologic correlations. Radiology 1984;151:697–702. 36. Teh BS, Bastasch MD, Wheeler TM, et al. IMRT for prostate cancer: Defining target volume based on correlated pathologic volume of disease. Int J Radiat Oncol Biol Phys 2003;56:184 – 191.