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Originally published as JCO Early Release 10.1200/JCO.2008.19.7707 on November 3 2008 © 2008 American Society of Clinical Oncology.
In Reply
Institut Gustave Roussy and University Paris Sud, Villejuif, France We read with great interest the letter by Vergote et al concerning our recently published article.1 Vergote et al made two comments.
The first comment concerns the theoretical potential impact of the interval between positron emission tomography combined with computed tomography (PET-CT) imaging (performed before initiating chemoradiotherapy [CRT]) and surgery (performed at the time of completion surgery) in the false-negative results of our study. This potential bias was discussed in our article.1 However, as mentioned in our discussion, this appears to be unlikely because two of the three patients with false-negative results had massive involvement (size of nodes The series we reported in Journal of Clinical Oncology was recently updated to April 2008 to present results at an international meeting. As of then, 54 patients with stage IB2-III disease had undergone PET-CT imaging that demonstrated negative uptake in the para-aortic area followed by a para-aortic lymphadenectomy. This nodal surgery was performed at the time of completion surgery (after CRT) in the majority of patients, but some had initially undergone laparoscopic para-aortic lymphadenectomy (therefore, just after PET-CT imaging and before the beginning of CRT), which then had been introduced as a routine surgical procedure at our institution (nine patients had initial laparoscopic staging before CRT). Six patients (11%) were found to have false-negative PET-CT imaging results. Details concerning the characteristics of these six patients are given in Table 1. Among them, one patient with 15 metastatic para-aortic nodes discovered at the time of surgery had an interval of 6 days between PET-CT and surgery. Given the shortness of the interval, this was a true false-negative PET-CT result.
Kang et al2 appear to corroborate the rate of false-negative results of PET-CT imaging by adding interesting data in their Letter to the Editor concerning our publication. They reported their own experience in correlating histology and PET-CT in patients undergoing surgery initially (before CRT). Of 24 patients reported with negative PET-CT imaging in the para-aortic area, two (8.3%) had histologically involved para-aortic nodes. This rate is similar to that reported in our series1 and that reported by Vergote et al. A possible explanation for the false-negative results of PET-CT imaging is the size of the metastatic nodes. In the experience of Vergote et al, four of nine patients with false-negative PET-CT results had micrometastatic nodes, and they were undetectable. But five patients had metastatic nodes smaller than 1 cm. Reporting the precise size of the largest metastatic nodes (ie, specifying whether nodal metastases were < 5 or > 5 mm) would have been helpful because the limit of spatial resolution of PET-CT imaging is 5 or 6 mm. In our series, of six patients with false-negative results (Table 1), five had nodal metastasis with capsular rupture, and four of them had nodal metastasis greater than 5 mm. Apart from the size of the target, other mechanisms (biologic or molecular) should therefore be explored to explain this false-negative rate. Whatever the explanation, these different data (which will be improved by the results of several ongoing studies) suggest that the false-negative rate of PET-CT imaging should be close to 10%. This would justify including surgical staging in the para-aortic area in patients with negative PET-CT imaging in the para-aortic area to precisely define the level of the CRT field. The second comment made by Vergote et al concerns the impact of such surgery on the survival of patients. Vergote et al reported interesting results on the survival of patients treated with extended-field CRT (including the para-aortic area) whose positive para-aortic nodes were detected after initial lymphadenectomy. Concerning the nine patients treated with this modality in their series, seven died as a result of their disease. Such disappointing results raise two questions. First, does initial staging surgery finally improve the survival of patients? Second, is extended-field CRT finally the best way to improve the survival of patients with positive para-aortic nodes? In fact, when we analyzed the outcomes of the patients reported by Vergote et al, we were surprised by the rapid lethal outcome in their patients: of seven patients who died of their disease, five died within 12 months (three of them within 6 months). This interval seems to be very short. Patient survival was not studied in our own series because the prognostic impact of para-aortic nodal involvement discovered at the time of CRT is worse than when this spread is discovered initially in patients.3
The most convincing data in the literature about the positive impact of staging surgery and extended-field radiation therapy are those recently reported by Leblanc and Querleu.4 In this major study of the largest number of patients submitted to surgical para-aortic staging and subsequent extended-field (chemotherapy) radiation therapy for positive para-aortic nodes, no survival difference was observed between patients with node-negative disease who received pelvic treatment alone and patients with microscopic nodal disease ( In 1998, in a study from the Gynecologic Oncology Group, Varia et al5 reported outcomes of patients treated with extended-field radiation therapy to the para-aortic area with concomitant chemotherapy because of nodal spread at this level: the 3-year overall survival rates were 50% and 39% in patients with stage I and II disease, respectively. These results are not so poor and suggest that, to date, the best modality for improving the survival of patients with positive para-aortic nodes (in the absence of other metastases) is extended-field radiation therapy (pelvic and para-aortic) with concomitant chemotherapy. How can we explain the differences between these survival results of the Varia et al5 and Leblanc et al4 series and the poor results reported by Vergote et al? In nine patients with false-negative results, three had stage IIIB disease. The survival of patients with stage III and para-aortic node involvement is lower than that of patients with stage I disease.5 Furthermore, in the Vergote et al series, of the seven patients with positive para-aortic nodes who died, five had adenocarcinoma lesions. All patients with adenocarcinoma and positive para-aortic nodes died as a result of the disease. Of four patients with a squamous cell tumor and positive para-aortic nodes, two were disease-free after 10 and 37 months of follow-up. This result suggests that the modality used to treat locally advanced adenocarcinoma (particularly in the subgroup of patients with positive para-aortic nodes) should perhaps be different from that used for squamous cell tumors. New treatment modalities (eg, CRT with conventional drugs combined with targeted therapy such as antiangiogenic drugs, the use of consolidation adjuvant chemotherapy after CRT, and so on) probably deserve to be investigated, in this subgroup of patients in particular. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Lorna Saint Ange for editing. NOTES published online ahead of print at www.jco.org on November 3, 2008 REFERENCES 1. Boughanim M, Leboulleux S, Rey A, et al: Histologic Results of para-aortic lymphadenectomy in patients treated for stage IB2-II cervical cancer with negative [18F] florodesoxyglucose positron emission tomography scans in the para-aortic area. J Clin Oncol 28:2558-2564, 2008 2. Kang S, Seo SS, Park SY: Occult para-aortic lymph node metastasis after negative PET-CT scan. J Clin Oncol doi:10.1200/JCO.2008.18.9928 [epub ahead of print on October 6, 2008] 3. Delpech Y, Haie-Meder C, Rey A, et al: Para-aortic involvement in stage IB2-II cervical carcinoma confined radiologically to the pelvic cavity treated using pelvic radiotherapy and concomitant chemotherapy. Ann Surg Oncol 14:3223-3231, 2007[CrossRef][Medline] 4. Leblanc E, Narducci F, Frumovitz M, et al: Therapeutic value of pretherapeutic extraperitoneal laparoscopic staging in locally advanced cervical carcinoma. Gynecol Oncol 105:304-311, 2007[CrossRef][Medline] 5. Varia MA, Bundy BN, Deppe G, et al: Cervical carcinoma metastatic to para-aortic nodes: Extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy—A Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 42:1015-1023, 1998[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10 mm) in the para-aortic area (with several involved nodes); furthermore, two of these patients had no residual disease in the cervix at histologic examination of the specimen removed at the time of completion surgery, suggesting that these patients had a radiosensitive tumor with a low risk of disease progression during treatment.
5 mm) managed with extended-field radiation therapy. Thus, the therapeutic impact of initial laparoscopic staging surgery and the benefit in terms of optimizing survival following extended-field chemoradiation therapy are particularly important for patients with small metastases in para-aortic nodes (who have a lower risk of occult distant metastasis).
