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© 2003 American Society for Clinical Oncology
In Reply:Veterans Administration Medical Center, Syracuse, NY We are appreciative of Dr Lawrence’s insightful comment on our article published in the March 15, 2003, issue of the Journal of Clinical Oncology. Dr Lawrence appropriately points out the potential therapeutic value of removal of mediastinal lymph nodes in the treatment of early-stage non–small-cell lung cancer (NSCLC). Based on his review of literature in prostate, cervical, and vulvar cancer, and as reviewed extensively in her editorial by Dr Sigurdson1 using breast cancer as a model, local nodal treatment with surgery and/or radiation therapy does correlate with improved locoregional control in a variety of epithelial malignancies and often translates to improved survival. With the information obtained from the aforementioned study, given its retrospective nature, nonhomogenous surgical treatment, and a wide temporal spread of patients, we are not able to demonstrate the therapeutic value of mediastinal lymph node dissection (MLND). When we compared patients treated with systematic sampling and those with MLND, no significant difference was noted in terms of survival between those groups, though the MLND group had a greater number of lymph nodes removed. We did suggest in our discussion that removal of a greater number of lymph nodes may offer a therapeutic advantage, but it is our opinion that appropriate tumor upstaging ("Will Rogers effect") is a more likely explanation. To convincingly demonstrate therapeutic value of lymphadenectomy, we should be able to demonstrate the following: (1) micrometastases exist in the draining lymph nodes that are not detected by standard histopathologic methods; (2) the presence of such micrometastases is associated with a higher tumor recurrence at least at the locoregional level; and (3) appropriate treatment of lymph nodes reduces disease recurrence rates and improves survival. In this regard, Dr Lawrence’s review of the literature instructive. The Gynecologic Oncology Group-037 trial concluded that "the addition of adjunctive groin and pelvic irradiation therapy after radical vulvectomy and inguinal lymphadenectomy proved superior to pelvic node resection"2. In this study, all patients underwent inguinal lymphadenectomy, but pelvic radiation did seem to confer additional benefit after inguinal lymphadenectomy. This suggested that despite lymphadenectomy, there was possibly residual disease that was responsive to the radiation therapy. Similarly, in the Gynecologic Oncology Group 092 trial, selected patients with stage IB cervical carcinoma who were treated with radical hysterectomy and pelvic lymphadenectomy were randomized to pelvic radiation therapy versus no further therapy. Adjuvant pelvic radiotherapy reduced the recurrences in this group of patients (88% v 79% recurrence-free survival at 2 years).3 Considering that all patients in this trial underwent pelvic lymphadenectomy, this study again indicates that radiation therapy adds to disease response despite adequate surgical therapy. This would suggest that lymphadenectomy, in and of itself, is not therapeutic in all patients. Similarly, the research quoted in prostate cancer suggests that adjuvant radiation therapy is superior to salvage radiation therapy. However, with the exception of one,4 all are retrospective series with the number of patients ranging from 61 to 146 participants, and all are based on a single institution’s experience. Data from prospective randomized trials are lacking in this area. Several investigators have evaluated the impact of occult tumor metastases detected by immunohistochemical or molecular techniques in lymph nodes in solid tumors. Kubuschok et al,5 found tumor cells in 21.6% of their patients with pT1–4, pN0–2, and M0 NSCLC in nodes reported as negative by conventional histopathology. They report a significantly reduced disease-free survival and overall survival in patients with disseminated tumor cells as determined by immunohistochemistry, including patients with pN0 tumors. Marchevsky et al, were also able to detect disseminated tumor cells in 5 of 33 pN0 NSCLC patients.6 However, they found no difference in survival in patients with pN0 tumors with or without evidence of occult nodal metastases. Similarly, Arhendt et al did not find occult metastases to affect survival in their cohort of patients using molecular techniques.7 Similar findings have also been reported in breast cancer studies.8 The deliberations and conclusions of a workshop "Detection and Measurement of Occult Disease for the Prognosis of Solid Tumors" were recently reported.9 As recommended by the workshop, participation in and results from prospective controlled randomized trials designed to assess prevalence, relationship to prognosis, and clinical utility of disseminated tumor metastases are needed in this area to arrive at definitive conclusions. The American College of Surgeon Oncology Group Z0040 trial titled "A Prospective Study of the Prognostic Significance of Occult Metastases in the Patient With Resectable Non–Small-Cell Lung Carcinoma," which is now enrolling patients with stage I, II, and IIIA NSCLC for operative pleural lavage, bone marrow aspiration, and lymphadenectomy, is an appropriate example of the same. The presence of occult metastases in the bone marrow, lymph nodes, and pleural lavage fluid will be compared with intermediate markers of disease progression and long-term disease-free and overall survival rates. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Sigurdson RE: Lymph node dissection: Is it diagnostic or therapeutic? J Clin Oncol 21:965–967, 2003 2. Homesley HD, Bundy BN, Sedlis A, et al: Radiation therapy versus pelvic lymph node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 68:733–740, 1986[Medline] 3. Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A GOG study. Gynecol Oncol 73:177–183, 1999[CrossRef][Medline] 4. Valicenti RK, Gomella LG, Ismail M, et al: Durable efficacy of early postoperative radiation therapy for high risk pT3N0 prostate cancer: The importance of radiation dose. Urology 52:1034–1040, 1998[CrossRef][Medline]
5. Kubuschok B, Passlick B, Izbicki JR, et al: Disseminated tumor cells in lymph nodes as a determinant for survival in surgically resected non–small-cell lung cancer. J Clin Oncol 17:19–24, 1999
6. Marchevsky AM, Qiao JH, Krajisnik S, et al: The prognostic significance of intranodal isolated tumor cells and micrometastases in patients with non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg 126:551–557, 2003
7. Ahrendt SA, Yang SC, Wu L, et al: Molecular assessment of lymph nodes in patients with resected stage I non-small cell lung cancer: Preliminary results of a prospective study. J Thorac Cardiovasc Surg 123:466–474, 2002
8. Braun S, Cevati BS, Assemi C, et al: Comparative analysis of micrometastasis to bone marrow and lymph nodes of node negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 19:1468–1475, 2001
9. Lugo TG, Braun S, Cote RJ, et al: Detection and measurement of occult disease for the prognosis of solid tumors. J Clin Oncol 21:2609–2615, 2003
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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