- Email: [email protected]
CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes
550
[2]
[3] [4]
[5]
Letters to the Editor a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 1996;23:40–7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: 2335–42. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123–9. Maroeska Te Loo D, Bosma N, Van Hinsbergh V, Span P, De Waal R, Clarijs R, et al. Elevated levels of vascular endothelial growth factor in serum of patients with D+ HUS. Pediatr Nephrol 2004;19:754–60.
Nicolas Chopin⁎ Jérôme Alexandre Charles Chapron Laurence Moachon François Goldwasser Gynécologie-Obstétrique II, Oncologie, Pharmacologie, Université René Descartes, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, CHU Cochin, Paris, France E-mail address: [email protected]. ⁎Corresponding author. Fax: +33 1 58 41 18 70. 26 January 2006 doi:10.1016/j.ygyno.2006.01.044
Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes To the Editor: In a small (n = 14), but well characterized group of patients, Bristow et al. provide important data regarding the limitations of PET/CT scanning in the evaluation of patients with ovarian cancer [1]. While in 20% of cases (3 of 14) the diagnostic procedure failed to detect extra-nodal intraperitoneal disease, almost 60% of individual lymph nodes histologically confirmed to contain cancer were not identified by the test. Of concern is not the outcome of the analysis, which clearly highlights the need for this expensive diagnostic test to undergo far more rigorous evaluation before it becomes a component of routine care in this malignancy [2], but rather is the interpretation of these results by the investigators. In the conclusion of the abstract, they write, “The high incidence of occult disease within the target nodal basins suggests that regional lymphadenectomy may be necessary for complete secondary cytoreduction of recurrent disease” [1].
How can the failure of a diagnostic test to define the extent of disease support more aggressive surgery for an unproven indication? This paper quotes retrospective series suggesting the clinical utility of “secondary cytoreduction”, noting that patients who appear to benefit from this management strategy have a superior performance status and longer treatment-free intervals than the “historical controls” they cite [1]. Of note, these “favorable” parameters are identical to those that predict for a secondary response to cytotoxic chemotherapy [3–5]. In the absence of data from a prospective phase 3 randomized trial, it must be firmly stated that it remains unknown if secondary cytoreductive surgery in ovarian cancer has an independent impact on survival, or if the ability to successfully perform a “complete” or “near complete” cytoreduction is simply associated with more favorable tumor biology. In fact, the one randomized trial performed in the United States by the Gynecologic Oncology Group (GOG) to examine the role of interval surgical cytoreduction (one type of “secondary” cytoreduction) in advanced ovarian cancer failed to reveal any survival benefit from this approach [6]. Further, a recently reported retrospective analysis of patients treated on a phase 3 GOG primary chemotherapy trial who underwent a “second-look” laparotomy, versus those individuals who did not undergo this procedure, also provided no evidence that what was done at this “secondary” surgery influenced outcome [7]. The GOG plans to directly examine the impact on survival of secondary cytoreduction in a soon-to-be-initiated randomized phase 3 trial in recurrent ovarian cancer. The results of this trial will be awaited with considerable interest, for it is certainly possible that a limited group of patients in this setting (e.g., good performance status, long-treatment free interval) might benefit from such surgery performed prior to the re-initiation of chemotherapy. However, in the complete absence of prospective randomized phase 3 trial data to support this general management approach, and the reasonable probability that any suggested benefits of aggressive secondary surgery are more related to inherent tumor biology rather than surgical skill, it is difficult to accept any rationale for proposing that more extensive surgery should be contemplated. The question to be asked is: Why should complete secondary cytoreduction of microscopic recurrent nodal disease be considered a rational “therapeutic objective”? References [1] Bristow RE, Giuntoli RI, Pannu HK, Schulick RD, Fishman EK, Wahl RL. Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal nodes. Gynecol Oncol 2005;99:294–300. [2] Markman M. The use of PET scans in ovarian cancer: a diagnostic technique in search of an indication. J Clin Oncol 2005;23:7385–7. [3] Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 1990;36:207–11. [4] Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9:389–93.
Letters to the Editor [5] Gronlund B, Hogdall C, Hansen HH, Engelholm SA. Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol 2001;83:128–34. [6] Rose P, Nerenstone S, Brady MF, Clarke-Pearson D, Olt G, Rubin SC, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489–97. [7] Greer BE, Bundy BN, Ozols RF, Fowler JM, Clarke-Pearson D, Burger RA, et al. Implications of second-look laparotomy in the context of optimally resected stage III ovarian cancer: a non-randomized comparison using an explanatory analysis: a Gynecologic Oncology Group study. Gynecol Oncol 2005;99:71–9.
Maurie Markman The University of Texas M.D. Anderson Cancer Center (Mail Box # 121), 1515 Holcombe Boulevard, Houston, TX 770030, USA E-mail address: [email protected]. Fax: +13 563 9586. 30 November 2005 doi:10.1016/j.ygyno.2006.01.054
Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes: Response to a letter from Dr. Maurie Markman To the Editor: Dr. Markman raises a number of important issues [1]. The first is the debate over the utility of secondary cytoreductive surgery for recurrent ovarian cancer. Similar to primary cytoreductive surgery for advanced ovarian cancer, the rationale for secondary cytoreductive surgery for selected patients with recurrent disease, defined as a disease-free interval of at least 6 to 12 months, is based on theoretical benefits supported by a large body of retrospective data indicating a statistically significant survival advantage associated with complete resection [2–8]. Clearly, our study of 14 highly selected patients with recurrent nodal disease was not designed to evaluate survival outcome. This point aside, Dr. Markman cites two published reports as evidence of the lack of survival benefit to secondary cytoreductive surgery [9,10]. Importantly, these two citations deal with “interval cytoreduction” after “induction chemotherapy” in a group of patients that were unable to be optimally debulked at primary surgery and a group of patients undergoing “second-look” surgery after achieving a complete clinical response to primary therapy and with no evidence of disease. We would suggest that surgical cytoreduction of platinumsensitive disease that recurs at a time remote from the initial treatment program is categorically different in terms of the clinical scenario and the relevant disease “biology” that Dr. Markman cites as a counterargument to the proposed benefits of secondary surgery. A second issue raised by Dr. Markman is the debate over whether the surgical outcome in patients with advanced or recurrent ovarian cancer is dependent on the “skill of the surgeon” or the “biology” of the disease. While the theoretical
551
framework of surgical expertise versus tumor biology may be the most aesthetically acceptable construct, it is undoubtedly too simplistic to reflect reality. In other words, as most clinicians can appreciate, the determinants of survival outcome of the individual patient with ovarian cancer are multi-factorial and include, but are not limited to, the general condition of the patient, the underlying tumor biology (e.g. degree of differentiation, inherent chemoresistance, etc.), and the adequacy of the surgical procedure(s). Surgery is an adjunct to effective chemotherapy, not a substitute. The argument that effective surgery is worthless in the patient with a favorable “tumor biology” is counterintuitive; such patients represent real opportunities for cure (or at least extended survival), and we as clinicians should use every available element in our therapeutic arsenal, within reason, to try and maximize survival outcome without compromising quality of life. A third issue raised by Dr. Markman is the perceived inaccuracy of combined PET/CT for detecting recurrent ovarian cancer in the retroperitoneal lymph nodes. In this context, it is worth reiterating the purpose and context of our study. Although it is a small series, the observations from the data point out that combined PET/CT can be useful in detecting isolated nodal recurrence of ovarian cancer when other diagnostic modalities have failed to localize disease. No conclusions regarding the potential benefit to the patient of early detection and treatment of recurrent disease can be drawn from this small study. Our data also indicate a high incidence of occult (or sub-clinical) disease with the nodal basin surrounding the target lymph node identified by combined PET/CT. One could view this as a “failure of a diagnostic test.” Alternatively, one could also view this observation as indicating that combined PET/CT is a sensitive marker, or surrogate indicator, of regional nodal metastasis, similar to the utility of sentinel node biopsy for breast cancer. In the case of a breast cancer patient with a positive sentinel lymph node, for example, a positive marker is taken as an indication for a more complete nodal excision to ensure satisfactory regional disease clearance. We are only advocating a similar approach to the patient with an apparent isolated nodal recurrence of ovarian cancer. Finally, Dr. Markman takes issue with our statement that complete secondary cytoreduction of microscopic recurrent nodal disease is a rational therapeutic objective. A report by Eisenkop and Spirtos that describes their experience with advanced-stage ovarian cancer patients and retroperitoneal lymph node metastasis highlights the potential significance of sub-clinical nodal disease [11]. Among patients in this series with nodal metastasis ≤10mm in maximal diameter, the nodal tissue was completely replaced by tumor in 83% of cases. This observation, coupled with data indicating that the maximum survival advantage from secondary cytoreduction is associated with complete cytoreduction of recurrent ovarian cancer, forms the basis for our recommendation for a regional lymphadenectomy [2–8]. It is almost assured that, in this highly selected patient population, the potential benefit of regional lymphadenectomy versus excision of grossly evident disease versus non-surgical treatment alone will never be addressed in a prospective randomized phase III clinical trial.
[2]
[3] [4]
[5]
Letters to the Editor a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 1996;23:40–7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: 2335–42. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005;23:2123–9. Maroeska Te Loo D, Bosma N, Van Hinsbergh V, Span P, De Waal R, Clarijs R, et al. Elevated levels of vascular endothelial growth factor in serum of patients with D+ HUS. Pediatr Nephrol 2004;19:754–60.
Nicolas Chopin⁎ Jérôme Alexandre Charles Chapron Laurence Moachon François Goldwasser Gynécologie-Obstétrique II, Oncologie, Pharmacologie, Université René Descartes, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, CHU Cochin, Paris, France E-mail address: [email protected]. ⁎Corresponding author. Fax: +33 1 58 41 18 70. 26 January 2006 doi:10.1016/j.ygyno.2006.01.044
Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes To the Editor: In a small (n = 14), but well characterized group of patients, Bristow et al. provide important data regarding the limitations of PET/CT scanning in the evaluation of patients with ovarian cancer [1]. While in 20% of cases (3 of 14) the diagnostic procedure failed to detect extra-nodal intraperitoneal disease, almost 60% of individual lymph nodes histologically confirmed to contain cancer were not identified by the test. Of concern is not the outcome of the analysis, which clearly highlights the need for this expensive diagnostic test to undergo far more rigorous evaluation before it becomes a component of routine care in this malignancy [2], but rather is the interpretation of these results by the investigators. In the conclusion of the abstract, they write, “The high incidence of occult disease within the target nodal basins suggests that regional lymphadenectomy may be necessary for complete secondary cytoreduction of recurrent disease” [1].
How can the failure of a diagnostic test to define the extent of disease support more aggressive surgery for an unproven indication? This paper quotes retrospective series suggesting the clinical utility of “secondary cytoreduction”, noting that patients who appear to benefit from this management strategy have a superior performance status and longer treatment-free intervals than the “historical controls” they cite [1]. Of note, these “favorable” parameters are identical to those that predict for a secondary response to cytotoxic chemotherapy [3–5]. In the absence of data from a prospective phase 3 randomized trial, it must be firmly stated that it remains unknown if secondary cytoreductive surgery in ovarian cancer has an independent impact on survival, or if the ability to successfully perform a “complete” or “near complete” cytoreduction is simply associated with more favorable tumor biology. In fact, the one randomized trial performed in the United States by the Gynecologic Oncology Group (GOG) to examine the role of interval surgical cytoreduction (one type of “secondary” cytoreduction) in advanced ovarian cancer failed to reveal any survival benefit from this approach [6]. Further, a recently reported retrospective analysis of patients treated on a phase 3 GOG primary chemotherapy trial who underwent a “second-look” laparotomy, versus those individuals who did not undergo this procedure, also provided no evidence that what was done at this “secondary” surgery influenced outcome [7]. The GOG plans to directly examine the impact on survival of secondary cytoreduction in a soon-to-be-initiated randomized phase 3 trial in recurrent ovarian cancer. The results of this trial will be awaited with considerable interest, for it is certainly possible that a limited group of patients in this setting (e.g., good performance status, long-treatment free interval) might benefit from such surgery performed prior to the re-initiation of chemotherapy. However, in the complete absence of prospective randomized phase 3 trial data to support this general management approach, and the reasonable probability that any suggested benefits of aggressive secondary surgery are more related to inherent tumor biology rather than surgical skill, it is difficult to accept any rationale for proposing that more extensive surgery should be contemplated. The question to be asked is: Why should complete secondary cytoreduction of microscopic recurrent nodal disease be considered a rational “therapeutic objective”? References [1] Bristow RE, Giuntoli RI, Pannu HK, Schulick RD, Fishman EK, Wahl RL. Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal nodes. Gynecol Oncol 2005;99:294–300. [2] Markman M. The use of PET scans in ovarian cancer: a diagnostic technique in search of an indication. J Clin Oncol 2005;23:7385–7. [3] Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 1990;36:207–11. [4] Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9:389–93.
Letters to the Editor [5] Gronlund B, Hogdall C, Hansen HH, Engelholm SA. Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol 2001;83:128–34. [6] Rose P, Nerenstone S, Brady MF, Clarke-Pearson D, Olt G, Rubin SC, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489–97. [7] Greer BE, Bundy BN, Ozols RF, Fowler JM, Clarke-Pearson D, Burger RA, et al. Implications of second-look laparotomy in the context of optimally resected stage III ovarian cancer: a non-randomized comparison using an explanatory analysis: a Gynecologic Oncology Group study. Gynecol Oncol 2005;99:71–9.
Maurie Markman The University of Texas M.D. Anderson Cancer Center (Mail Box # 121), 1515 Holcombe Boulevard, Houston, TX 770030, USA E-mail address: [email protected]. Fax: +13 563 9586. 30 November 2005 doi:10.1016/j.ygyno.2006.01.054
Combined PET/CT for detecting recurrent ovarian cancer limited to retroperitoneal lymph nodes: Response to a letter from Dr. Maurie Markman To the Editor: Dr. Markman raises a number of important issues [1]. The first is the debate over the utility of secondary cytoreductive surgery for recurrent ovarian cancer. Similar to primary cytoreductive surgery for advanced ovarian cancer, the rationale for secondary cytoreductive surgery for selected patients with recurrent disease, defined as a disease-free interval of at least 6 to 12 months, is based on theoretical benefits supported by a large body of retrospective data indicating a statistically significant survival advantage associated with complete resection [2–8]. Clearly, our study of 14 highly selected patients with recurrent nodal disease was not designed to evaluate survival outcome. This point aside, Dr. Markman cites two published reports as evidence of the lack of survival benefit to secondary cytoreductive surgery [9,10]. Importantly, these two citations deal with “interval cytoreduction” after “induction chemotherapy” in a group of patients that were unable to be optimally debulked at primary surgery and a group of patients undergoing “second-look” surgery after achieving a complete clinical response to primary therapy and with no evidence of disease. We would suggest that surgical cytoreduction of platinumsensitive disease that recurs at a time remote from the initial treatment program is categorically different in terms of the clinical scenario and the relevant disease “biology” that Dr. Markman cites as a counterargument to the proposed benefits of secondary surgery. A second issue raised by Dr. Markman is the debate over whether the surgical outcome in patients with advanced or recurrent ovarian cancer is dependent on the “skill of the surgeon” or the “biology” of the disease. While the theoretical
551
framework of surgical expertise versus tumor biology may be the most aesthetically acceptable construct, it is undoubtedly too simplistic to reflect reality. In other words, as most clinicians can appreciate, the determinants of survival outcome of the individual patient with ovarian cancer are multi-factorial and include, but are not limited to, the general condition of the patient, the underlying tumor biology (e.g. degree of differentiation, inherent chemoresistance, etc.), and the adequacy of the surgical procedure(s). Surgery is an adjunct to effective chemotherapy, not a substitute. The argument that effective surgery is worthless in the patient with a favorable “tumor biology” is counterintuitive; such patients represent real opportunities for cure (or at least extended survival), and we as clinicians should use every available element in our therapeutic arsenal, within reason, to try and maximize survival outcome without compromising quality of life. A third issue raised by Dr. Markman is the perceived inaccuracy of combined PET/CT for detecting recurrent ovarian cancer in the retroperitoneal lymph nodes. In this context, it is worth reiterating the purpose and context of our study. Although it is a small series, the observations from the data point out that combined PET/CT can be useful in detecting isolated nodal recurrence of ovarian cancer when other diagnostic modalities have failed to localize disease. No conclusions regarding the potential benefit to the patient of early detection and treatment of recurrent disease can be drawn from this small study. Our data also indicate a high incidence of occult (or sub-clinical) disease with the nodal basin surrounding the target lymph node identified by combined PET/CT. One could view this as a “failure of a diagnostic test.” Alternatively, one could also view this observation as indicating that combined PET/CT is a sensitive marker, or surrogate indicator, of regional nodal metastasis, similar to the utility of sentinel node biopsy for breast cancer. In the case of a breast cancer patient with a positive sentinel lymph node, for example, a positive marker is taken as an indication for a more complete nodal excision to ensure satisfactory regional disease clearance. We are only advocating a similar approach to the patient with an apparent isolated nodal recurrence of ovarian cancer. Finally, Dr. Markman takes issue with our statement that complete secondary cytoreduction of microscopic recurrent nodal disease is a rational therapeutic objective. A report by Eisenkop and Spirtos that describes their experience with advanced-stage ovarian cancer patients and retroperitoneal lymph node metastasis highlights the potential significance of sub-clinical nodal disease [11]. Among patients in this series with nodal metastasis ≤10mm in maximal diameter, the nodal tissue was completely replaced by tumor in 83% of cases. This observation, coupled with data indicating that the maximum survival advantage from secondary cytoreduction is associated with complete cytoreduction of recurrent ovarian cancer, forms the basis for our recommendation for a regional lymphadenectomy [2–8]. It is almost assured that, in this highly selected patient population, the potential benefit of regional lymphadenectomy versus excision of grossly evident disease versus non-surgical treatment alone will never be addressed in a prospective randomized phase III clinical trial.