|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology
Lymph Node Dissection: Is It Diagnostic or Therapeutic?Fox Chase Cancer Center, Philadelphia, PA SURGERY IS the most effective therapy for most solid tumors. The principles of surgical resection of a cancer require removal of the affected site (with adequate margins) and the draining lymph nodes en bloc. There have been two opposing views regarding the role of lymphadenectomy in patients. The traditional Halsted view espouses that lymphadenectomy is important for staging and survival. The Cady-Fisher view counters that cancer is a systemic disease at inception and that the lymphadenectomy is merely useful for staging and does not affect survival. In this issue, Gajra et al1 retrospectively study the effect of lymph node sampling compared with lymph node dissection on staging and survival. For most potentially curable cancers, involvement of the lymph nodes is the single most significant prognostic factor. The operation performed and the surgeon who performs it (the adequacy of the resection) are also believed to be important factors. The concept of the surgeon as a source of variation in outcomes is not new. Many authors have shown that a surgeon’s experience and case volume affect mortality and morbidity of operations. Luft2 demonstrated that hospitals with greater surgical experience have better outcomes with open-heart surgery. The survival of patients undergoing pancreatic resection for malignancy has been correlated with hospital volume and thus, surgeon experience. Lieberman3 reviewed the outcome of patients undergoing either a pancreaticoduodenectomy or total pancreatectomy for malignancy in New York state. In this study, hospitals were grouped by case volume during an 8-year period. When adjusted for differences in patient characteristics such as age, sex, race, admission status, and year of surgery, the mortality rates were 18.9% for low-volume (10 to 50 cases in 8 years) and 5.5% for high-volume (> 80 cases in 8 years) centers. Simunovic et al4 showed similar volume-outcome results for patients undergoing resection of a pancreatic malignancy in the Canadian health care system. Demonstrating the influence of surgical expertise on long-term survival after cancer operations has been more difficult. A decrease in local recurrence is associated with improved surgical technique, but improvements in local recurrence rates do not always translate into improved survival. The outcome of patients undergoing resection for rectal cancer has been linked to the volume of cases or the specific training of the surgeon. Lane et al5 performed a survey of the members of the Association of Coloproctology of Great Britain and Ireland and found that cancer-specific survival improved and local recurrence decreased when a specialist performed the operation. The survival benefit from specialization was demonstrated only for patients with Dukes’ C lesions. A decline in local failure rate from 26% to 11% was associated with an improved 3-year survival. One potentially quantifiable surrogate marker for adequacy of surgical resection has been the number of lymph nodes removed by the surgeon and examined by the pathologist. The effect of the number of lymph nodes removed and examined has an inverse relationship with overall survival in many solid tumors. When improved survival correlates with increasing numbers of lymph nodes reported by the pathologist, three factors are potentially involved: (1) a diminished risk of local and regional recurrence may result from a more extensive lymphadenectomy, which yields more lymph nodes in the specimen; (2) the surgeon who performs a more complete node dissection may also provide better cancer care in all respects (including preoperative staging and a more thorough intraoperative evaluation of the thorax, abdomen, and pelvis) and may secure wider margins around the tumor; or (3) a more thorough examination of the specimen by the pathologist may result in more accurate staging. It has not been possible to assign a mechanism for improved outcome from any single study demonstrating improved survival with increased node count. In an analysis of more than 3,400 colon cancer patients treated in an intergroup adjuvant chemotherapy study, the number of lymph nodes analyzed strongly correlated with overall and disease-free survival.6 When the number of nodes involved was controlled for, survival increased as the number of nodes recovered increased. Even when no nodes were involved, overall survival improved as more nodes were recovered. When more than 40 lymph nodes were examined, as opposed to fewer than 10 nodes examined, there was a 23% improvement in 5-year survival. A similar trend was noted in invasive bladder cancer.7 In both node-negative and node-positive patients, the overall survival increased with an increasing number of lymph nodes reported. The authors determined that at least nine nodes should be studied to define lymph node status accurately. In breast cancer, the number of axillary lymph nodes examined has long been known to affect both staging and survival. Fisher et al8 reported 5-year survival rates for patients with N1 disease of 44% when one to five nodes were examined, 58% when six to 10 nodes were examined, and 68% when 11 to 15 nodes were examined. Other authors have confirmed these findings.9–11 Fowble et al12 found that in treating patients with T1 and T2 tumors and one to three positive nodes, 19 to 20 lymph nodes must be reported to assign stage with 90% accuracy. The effect on staging of the number of nodes examined may improve survival through a Will Rogers effect13 alone. Demonstrating an effect of more thorough surgical resection on survival is more difficult. The disease studied should be one in which outcome is not dominated by early distant disease progression and in which local recurrence has an opportunity to produce fatal metastases. Early breast cancer represents a reasonable model for such biologic behavior. The National Surgical Adjuvant Breast and Bowel Project B-04 trial14 compared radical mastectomy both to a simple mastectomy and to simple mastectomy with radiation therapy. The study did not demonstrate a difference in survival. However, many patients who were supposed to undergo mastectomy alone had lymph nodes removed. This study, inadequately powered to demonstrate a difference, is often discussed (wrongly) as demonstrating equivalence. The National Surgical Adjuvant Breast and Bowel Project B-0615 trial compared total mastectomy with partial mastectomy and axillary dissection with or without radiation therapy. In the report of the 20-year follow-up, the lumpectomy group that did not receive radiation therapy had a significantly higher local recurrence rate (39.2% v 14.3%) and, ultimately, a statistically significant increase in distant metastases. This survival benefit from improved local control was not observed with earlier analysis and was most significant in those who had negative surgical margins with the lumpectomy. Of note, death from distant metastases that result from local recurrences may not occur for many years. Long-term follow-up is imperative, as discussed by Hellman.16 Two randomized studies addressed the role of radiation therapy in treating premenopausal women who received cyclophosphamide, methotrexate, and fluorouracil chemotherapy after modified radical mastectomy. The British Columbian17 and Danish18 prospective randomized studies presented 15-year results comparing results with or without radiation therapy. Both studies demonstrated a reduction in local recurrence with radiation therapy and a subsequent improvement in overall survival. In the Danish trial,18 patients with one to three positive nodes had a 30% locoregional recurrence rate, compared with 42% for patients with four or more positive nodes. Half of the recurrences were in the axilla, and the median number of nodes removed and examined was seven. The overall survival improved from 45% to 54% by the addition of radiation therapy. In the British Columbian study,17 the locoregional recurrence in the one to three node-positive group was 33%, and in the four or more node-positive group the locoregional recurrence was 46%. Radiation resulted in a 29% reduction in mortality from breast cancer at 15 years. Early results revealed no differences in cancer-specific survival, but the women receiving regional radiation therapy experienced a long-term survival advantage. This indicates that locoregional treatment prevents recurrence from generating fatal metastases. Fowble et al12 applied their model discussed above to the data from the British Columbian and Danish trials. They reported that for T1N1 tumors, a minimum of 19 to 20 nodes are required to predict with 90% probability the true axillary stage. Using their rubric, they noted that a patient with a T1 tumor with two or three positive nodes out of seven examined would have a 55% or 93% probability, respectively, of actually having four or more positive nodes. For T2 tumors, the risk of having four or more nodes positive when two or three nodes were reported positive by the pathologist was 62% and 94%, respectively. Hence, many women believed to have few involved lymph nodes would actually have a natural history and recurrence rates comparable to that of women with four or more nodes involved. Similar results could be predicted in the British Columbian series, in which a median of 11 nodes were removed. In a Southeastern Oncology Group study of postmastectomy radiation therapy,19 all patients had more than 10 nodes examined, and the locoregional recurrence rate was 10% among patients receiving cyclophosphamide, methotrexate, fluorouracil, and postmastectomy radiation. In a similar study, recently updated by the Eastern Cooperative Oncology Group,20 the median number of nodes retrieved was 15, and the locoregional recurrence in patients with one to three positive nodes was 13% among patients who did not receive radiation. It is reasonable to conclude from subset analysis (to isolate patient groups treated similarly to those in Denmark and Canada) of large randomized studies that in both the Danish and the British Columbian studies, there was a high likelihood of involved nodes remaining in the axilla, resulting in the higher locoregional recurrence rate. These patients may then have behaved similarly to a group at higher risk of a chest wall recurrence—those with four or more positive nodes. Among these premenopausal women with one to three positive nodes (with median of only seven to 11 removed), postmastectomy radiation therapy prevented locoregional recurrences. Most important, both studies indicate a strong adverse effect of locoregional recurrence rates on overall survival. These data indicate that adequate treatment of the axilla is important. A thorough axillary dissection may be sufficient for both staging and treatment. With a less complete axillary dissection, radiation therapy may represent an important adjuvant regional treatment in addition to systemic therapy. How best to treat the axilla is being addressed in ongoing studies of sentinel node lymphadenectomy alone in node-positive patients. A meta-analysis of 18 randomized trials involving more than 6,300 pre- and postmenopausal women considered the risk of locoregional recurrence and survival after mastectomy.21 The results of the analysis were consistent with the conclusions of the Danish and British Columbian studies. Radiation therapy after mastectomy decreased locoregional recurrence and improved disease-free and overall survival. With this perspective, Gajra et al1 proposed that surgical removal and pathologic evaluation of lymph nodes in stage I non–small-cell lung cancer will influence both time to recurrence and overall survival. In this retrospective study, patients were allocated to one of three groups: random lymph node sampling, systematic sampling by node station, or complete mediastinal lymph node dissection. Thus, the authors attempted to separate the effect of more comprehensive staging through pathologic evaluation from that of possible therapeutic lymphadenectomy; that is, to separate the effect of the pathologist from the effect of the surgeon. Within the limits of a retrospective study, the data indicate that both the pathologist and the surgeon influence staging and outcome. The pathologist can have a significant effect on staging by thorough node inspection. The surgeon may have an effect on survival through several mechanisms. The surgeon may perform a better cancer operation, with wide, clear margins, and a more complete removal of involved nodes. The surgeon may have improved results because a more thorough inspection of the thorax identified metastatic disease and, thus, improved patient staging. Last, the surgeon may have improved results because a more thorough preoperative investigation identified metastatic disease, and again improved patient staging. The American College of Surgery Oncology Group is examining the effect of mediastinal dissection in lung cancer therapy and will provide important additional information. The need to secure and retain local and regional control of solid tumors will assume increasing importance as systemic therapy improves and reduces death from distant metastases. The role of pathologic staging for many cancers also may change because sentinel node mapping should allow the pathologist to examine minutely the first nodal echelon. Many intergroup trials are examining the effect of sentinel node identification on staging and the results of treatment. For decades, the oncology community has focused clinical research on adjuvant therapy in an effort to prevent distant metastases. For many cancers, the effect of local recurrence on survival has been downplayed, or even denied. However, prevention of locoregional recurrence remains an important goal. Even otherwise indolent local and regional disease represents a threat to patients whose low-volume distant tumor has been controlled by systemic therapy. Still better regional treatment of cancer should afford a survival advantage. Whether this is best pursued through lymphadenectomy or through a combination of resection with radiation is as yet unknown, but the effect of regional metastases on survival cannot be ignored. REFERENCES
1. Gajra A, Newman N, Gamble G, et al: Impact of number of lymph nodes sampled on outcome in patients with Stage I non-small cell lung cancer. J Clin Oncol 21:1029–1034, 2003 2. Luft HS, Bunker JP, Enthoven AC: Should operations be regionalized? The empirical relation between surgical volume and mortality. N Engl J Med 301:1364–1369, 1979[Abstract] 3. Lieberman M, Kilburn H, Lindsey M, et al: Relation of perioperative deaths to hospital volume among patients undergoing pancreatic resection for malignancy. Ann Surg 222:638–645, 1995[Medline] 4. Simunovic M, To T, Theriault M, et al: Relation between hospital surgical volume and outcome for pancreatic resection for neoplasm in a publicly funded health care system. Can Med Assoc J 160:643–648, 1999[Abstract] 5. Lane R, Thompson M, Whatley P, et al: Effect of specialization on outcome in patients having surgery for rectal cancer. Dis Colon Rectum 42:A6, 1999 6. LeVoyer TE, Sigurdson ER, Hanlon AL, et al: Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of INT-0089. J Clin Oncol, in press. 7. Herr HW, Bochner BH, Dalbagni G, et al: Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 167:1295–1298, 2002[CrossRef][Medline] 8. Fisher B, Slack NH: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg Gynecol Obstet 131:79–88, 1970[Medline] 9. Wilking N, Rutqvist LE, Cartensen J, et al: Prognostic significance of axillary nodal status in primary breast cancer in relation to the number of resected nodes. Acta Oncol 31:29–35, 1992[Medline] 10. Korzzeniowski S, Dyba T, Skolyszewski J: Classical prognostic factors for survival and loco-regional control in breast cancer patients treated with radical mastectomy alone. Acta Oncol 33:759–765, 1994[Medline] 11. Kahlert SD, Konecny G, Nestle-Kraemling C, et al: Extent of axillary lymph node dissection: A source of misinterpretation but not a prognostic factor. Proc Am Soc Clin Oncol 18:76a, 1999 (abstr 443) 12. Iyer RV, Hanlon A, Fowble B: Accuracy of the extent of axillary nodal positivity related to primary tumor size, number of involved nodes, and number of nodes examined. Int J Radiat Oncol Biol Phys 47:1177–1183, 2000[CrossRef][Medline] 13. Feinstein AR, Sosin DM, Wells CK: The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 312:1604–1608, 1985[Abstract]
14. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567–575, 2002
15. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy with irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241, 2002
16. Hellman S: Stopping metastases at their source. N Engl J Med 337:996–997, 1997
17. Ragaz J, Jackson SM, Plenderleith IA, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956–962, 1997
18. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949–955, 1997 19. Velez-Garcia E, Carpenter JT Jr, Moore M, et al: Post surgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: A Southeastern Cancer Study Group Trial. Eur J Cancer Clin Oncol 28A:1833–1837, 1992
20. Recht A, Gray R, Davidson NE, et al: Local-regional failure ten years following mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689–1700, 1999
21. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220–1229, 2000
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
