- Email: [email protected]
Letter-to-the Editor "Trends in treatment of advanced epithelial ovarian cancer in the Medicare population”
Gynecologic Oncology 125 (2012) 278–281
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Letters to the Editor Trends in treatment of advanced epithelial ovarian cancer in the Medicare population To the Editor, In a recent analysis paper in Gynecologic Oncology entitled, “Trends in treatment of advanced ovarian cancer in the Medicare population” several statements and general conclusions drawn by the authors are worthy of additional discussion [1]. First, the authors describe the “practice” of neoadjuvant chemotherapy as being “controversial and generally reserved for women who are poor surgical candidates” and conclude that “despite recent publications emphasizing the importance of primary debulking surgery in advanced ovarian cancer we observed a striking decrease in the use of primary debulking surgery from 1995 to 2005” [1]. Unfortunately, the authors fail to acknowledge the publication earlier this year of a landmark evidence-based randomized phase 3 trial that revealed not only the general therapeutic equivalence of neoadjuvant chemotherapy (progression-free and overall survival) in advanced epithelial ovarian cancer but the actual demonstrated superiority of this alternative strategy as regards treatment-related morbidity and mortality [2]. Thus, the question to be asked of the authors is that rather than failing to adhere to “the evidence” is it possible the identified trend is actually “evidence” that the community of oncologists in the United States is quite reasonably employing what “evidence-based” data actually indicate is quite reasonable cancer care in this older (Medicare) population? Second, the hypothesis that six cycles of chemotherapy should characterize appropriate ovarian cancer management is questionable, since it is well-recognized that even in the clinical trials setting (with the most favorable patient populations) only 60–70% of patients achieve an objective response to platinum-based chemotherapy [3– 5]. As a result, and particularly in this older population, one can rationally suggest that cytotoxic therapy in approximately 30–40% of individuals may be quite reasonably discontinued after a total of only 2–4 treatment cycles (following evidence of the failure of the cancer to respond to therapy). Finally, for the same reason just noted, it is uncertain how the investigators can characterize the performance of cytoreductive surgery following neoadjuvant chemotherapy in approximately one-third of the patient population as suggesting inadequate care. Considering the known failure rate of primary platinum-based chemotherapy (30–40%) and the rational conclusion that it may be quite reasonable to consider continuation of chemotherapy in an elderly patient with co-morbidity who achieves a major objective and subjective response to cytotoxic drugs (reserving surgery for carefully-considered palliative strategies), it is uncertain how one can assume that a substantially greater percentage of patients than actually observed in this analysis should have undergone an attempt at aggressive surgical cytoreduction. It is fully appreciated that any attempt to employ large population-based retrospective data to evaluate the quality-ofcare being provided to a population is fraught with great hazard. Further, there is no attempt here to even remotely suggest the
care of women with ovarian cancer cannot be improved. However, based on concerns with the above noted assumptions and conclusions as well as existing very solid data regarding the utility of the neoadjuvant approach [2], it is appropriate to challenge the assertion that the oncology community is somehow failing to follow “evidence-based guidelines” for the management of advanced ovarian cancer. Conflict of interest statement The author has no conflicts of interest to declare.
References [1] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecol Oncol 2011;122:100–6. [2] Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53. [3] Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian cancer. J Natl Cancer Inst 2004;96:1682–91. [4] Spriggs DR, Brady MF, Vaccarello L, Clark-Pearson DL, Burger RA, Mannel R, et al. Phase III randomized trial of intravenous cisplatin plus 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a gynecologic oncology group study. J Clin 2007;25:4466–71. [5] Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106–15.
Maurie Markman Cancer Treatment Centers of America, Eastern Regional Medical Center, 1331 East Wyoming Avenue, Philadelphia, PA 19124, USA E-mail address: [email protected].
doi:10.1016/j.ygyno.2011.11.047
Letter-to-the Editor "Trends in treatment of advanced epithelial ovarian cancer in the Medicare population” To the Editor, We would like to thank Dr Markman for his comments regarding our recently published manuscript [1] and thank the editors of Gynecologic Oncology for the opportunity to respond to Dr. Markman's remarks. The purpose of this analysis was to evaluate treatment received by elderly women diagnosed with advanced ovarian cancer in the US from 1995 to 2005. The study aimed to determine the frequency with which women were treated according to the accepted standard of care at the time, a combination of cytoreductive surgery and platinum based chemotherapy as published by the National Comprehensive Cancer Network (NCCN) guidelines and NIH consensus statement [2]. In
Letters to the Editor
this analysis we were not attempting to validate these standards of care or define the role of neoadjuvant chemotherapy in this population. Rather, we aimed to describe the patterns of care observed and considered care as to have met the “standard” if any combination of surgery and 6 cycles of chemotherapy were received. Sequencing of therapy was described in the results, but all women receiving surgery and at least 6 cycles chemotherapy in any order were combined as a single group for the analysis. In this way we sought to better understand the care that was being delivered in the population and identify factors associated with observed variation from what was considered by many to be the standard of care. We agree that the role of neoadjuvant chemotherapy in the treatment of advanced ovarian cancer has recently become supported by the aforementioned trial published by Vergote et al. The results of this trial were published in 2010, and as such would not have influenced practice during the study period, and so we did not discuss this trial in this paper examining patterns of care from 1995 to 2005. However, we were also interested in examining outcomes associated with the use of neoadjuvant chemotherapy in the population and have recently published our findings as a separate manuscript [3]. It is interesting to note that in the trial by Vergote et al. which included only patients with extensive stage IIIC and IV ovarian cancers, 88% of patient treated with neoadjuvant chemotherapy were able to undergo surgical debulking, this supporting the notion that the observed 32% in our analysis was surprisingly low. Clearly an aggressive surgical operation and 6 cycles of cytotoxic chemotherapy in any sequence would not be the appropriate care for 100% of elderly women with advanced ovarian cancer. As discussed in our conclusions, many of the patients in our population were likely too ill or may have had progressive disease during treatment that would make “guideline” therapy inappropriate. Or data was limited by an inability to determine with accurate clinical reasons why care was not administered, and as such we refrained from making assumptions or strong conclusions about this based on these data. Despite this limitation, the finding that over 60% of women did not receive the standard of care as defined by the guidelines clearly supports the notion that there is significant room for improvement.
Conflict of interest statement The authors have no conflicts of interest to report.
References [1] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecol Oncol 2011;122:100–6. [2] National Institutes of Health Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up. Gynecol Oncol 1994;55:S4–S14. [3] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Neoadjuvant chemotherapy in the Medicare cohort with advanced ovarian cancer. Gynecol Oncol 2011;123:461–6.
Melissa M. Thrall * Heidi J. Gray Barbara A. Goff Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA, USA ⁎Corresponding author at: University of Washington School of Medicine, Department of Obstetrics and Gynecology Box 356460, Seattle WA 98195-6460, USA. Fax: +1 206 543 3915. E-mail address: [email protected].
doi:10.1016/j.ygyno.2011.12.451
279
Re: “Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multi-institutional phase II trial.” — Proposal of a clinical trial of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced ovarian cancer, the CHORINE study. Keywords: Epithelial ovarian cancer Cytoreductive surgery Hyperthermic intraperitoneal chemotherapy
To the Editor, We read with great interest the article by Deraco et al. [1] reporting the results of a multicenter phase II trial using cytoreductive surgery (CRS) and closed-abdomen hyperthermic intraoperative peritoneal chemotherapy (HIPEC) with cisplatin and doxorubicin in front-line treatment of epithelial ovarian cancer (EOC). The authors accrued 26 patients over 6 years in four different Italian centers, achieving macroscopically complete cytoreduction in 15 patients and only minimal residual disease (≤2.5 mm) in the remaining 11. Although major complications occurred in four patients, including one postoperative death, 25 of the 26 patients started systemic chemotherapy within a median of 46 days after surgery and noticeable five-year overall survival (60.7%) and progression-free survival (15.2%) have been obtained. These results are encouraging and accord with the available literature: nevertheless, in absence of a phase III trial, some considerations should be done before suggesting that CRS+HIPEC could be a valid strategy for upfront treatment of advanced EOC. First, nearly 70% of patients with EOC are diagnosed with advanced stage disease (stage III or IV), due to the non-specific nature of its early symptoms and disease progression. It is well known that primary CRS followed by platinum-based systemic adjuvant chemotherapy, when indicated, is the mainstay of treatment for EOC: in this setting, the aim of primary surgery is to remove as much tumor as possible (possibly all the tumor), because the amount of residual tumor is one of the most important prognostic factors for survival of women with EOC. Although optimal cytoreduction is usually defined as a residual tumor less than 1–2 cm, the evidence from literature is that the achievement of optimal (and better complete) cytoreduction, mainly in advanced EOC, is not always possible, due to extent of disease at time of presentation, medical co-morbidities, and experience of the surgeon [2]. Second, although not performing optimal and complete CRS results in losing the chance for improved survival, it has to be pointed out that radical surgery, especially in very advanced cases, is associated to a high incidence of postoperative morbidity and mortality [3] and could be even increased by the HIPEC procedure [4]. HIPEC remains a burdensome procedure: every effort is needed, before performing this procedure, to select which patients will achieve the maximum benefit from it. Last, it is well known that, although the majority of patients with EOC (up to 80%) respond to first-line platinum based chemotherapy, 20% of them are resistant or refractory. According to these data, the direct administration of high dose HIPEC on residual tumor cells after upfront CRS for advanced EOC would be offered to a certain percentage of women with insensitive chemoresistant tumor cells. Even if not detailed in the article by Deraco et al. [1], the survival curve shows that almost 30% of the patients recurred at one year. It is reasonable to suppose that these patients were not chemo-sensitive patients. HIPEC should be active on chemosensitive cells and the procedure could be avoided in women with insensitive tumor cells. Neoadjuvant chemotherapy (NACT) [5] followed by CRS+HIPEC, valuing the patients' response to NACT, could be a strategy to select for HIPEC only the patients who show chemosensitivity. There are few studies, reported in thirteen papers plus the one of Deraco and colleagues [1] in the literature (the list of these references
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Letters to the Editor Trends in treatment of advanced epithelial ovarian cancer in the Medicare population To the Editor, In a recent analysis paper in Gynecologic Oncology entitled, “Trends in treatment of advanced ovarian cancer in the Medicare population” several statements and general conclusions drawn by the authors are worthy of additional discussion [1]. First, the authors describe the “practice” of neoadjuvant chemotherapy as being “controversial and generally reserved for women who are poor surgical candidates” and conclude that “despite recent publications emphasizing the importance of primary debulking surgery in advanced ovarian cancer we observed a striking decrease in the use of primary debulking surgery from 1995 to 2005” [1]. Unfortunately, the authors fail to acknowledge the publication earlier this year of a landmark evidence-based randomized phase 3 trial that revealed not only the general therapeutic equivalence of neoadjuvant chemotherapy (progression-free and overall survival) in advanced epithelial ovarian cancer but the actual demonstrated superiority of this alternative strategy as regards treatment-related morbidity and mortality [2]. Thus, the question to be asked of the authors is that rather than failing to adhere to “the evidence” is it possible the identified trend is actually “evidence” that the community of oncologists in the United States is quite reasonably employing what “evidence-based” data actually indicate is quite reasonable cancer care in this older (Medicare) population? Second, the hypothesis that six cycles of chemotherapy should characterize appropriate ovarian cancer management is questionable, since it is well-recognized that even in the clinical trials setting (with the most favorable patient populations) only 60–70% of patients achieve an objective response to platinum-based chemotherapy [3– 5]. As a result, and particularly in this older population, one can rationally suggest that cytotoxic therapy in approximately 30–40% of individuals may be quite reasonably discontinued after a total of only 2–4 treatment cycles (following evidence of the failure of the cancer to respond to therapy). Finally, for the same reason just noted, it is uncertain how the investigators can characterize the performance of cytoreductive surgery following neoadjuvant chemotherapy in approximately one-third of the patient population as suggesting inadequate care. Considering the known failure rate of primary platinum-based chemotherapy (30–40%) and the rational conclusion that it may be quite reasonable to consider continuation of chemotherapy in an elderly patient with co-morbidity who achieves a major objective and subjective response to cytotoxic drugs (reserving surgery for carefully-considered palliative strategies), it is uncertain how one can assume that a substantially greater percentage of patients than actually observed in this analysis should have undergone an attempt at aggressive surgical cytoreduction. It is fully appreciated that any attempt to employ large population-based retrospective data to evaluate the quality-ofcare being provided to a population is fraught with great hazard. Further, there is no attempt here to even remotely suggest the
care of women with ovarian cancer cannot be improved. However, based on concerns with the above noted assumptions and conclusions as well as existing very solid data regarding the utility of the neoadjuvant approach [2], it is appropriate to challenge the assertion that the oncology community is somehow failing to follow “evidence-based guidelines” for the management of advanced ovarian cancer. Conflict of interest statement The author has no conflicts of interest to declare.
References [1] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecol Oncol 2011;122:100–6. [2] Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53. [3] Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian cancer. J Natl Cancer Inst 2004;96:1682–91. [4] Spriggs DR, Brady MF, Vaccarello L, Clark-Pearson DL, Burger RA, Mannel R, et al. Phase III randomized trial of intravenous cisplatin plus 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a gynecologic oncology group study. J Clin 2007;25:4466–71. [5] Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106–15.
Maurie Markman Cancer Treatment Centers of America, Eastern Regional Medical Center, 1331 East Wyoming Avenue, Philadelphia, PA 19124, USA E-mail address: [email protected].
doi:10.1016/j.ygyno.2011.11.047
Letter-to-the Editor "Trends in treatment of advanced epithelial ovarian cancer in the Medicare population” To the Editor, We would like to thank Dr Markman for his comments regarding our recently published manuscript [1] and thank the editors of Gynecologic Oncology for the opportunity to respond to Dr. Markman's remarks. The purpose of this analysis was to evaluate treatment received by elderly women diagnosed with advanced ovarian cancer in the US from 1995 to 2005. The study aimed to determine the frequency with which women were treated according to the accepted standard of care at the time, a combination of cytoreductive surgery and platinum based chemotherapy as published by the National Comprehensive Cancer Network (NCCN) guidelines and NIH consensus statement [2]. In
Letters to the Editor
this analysis we were not attempting to validate these standards of care or define the role of neoadjuvant chemotherapy in this population. Rather, we aimed to describe the patterns of care observed and considered care as to have met the “standard” if any combination of surgery and 6 cycles of chemotherapy were received. Sequencing of therapy was described in the results, but all women receiving surgery and at least 6 cycles chemotherapy in any order were combined as a single group for the analysis. In this way we sought to better understand the care that was being delivered in the population and identify factors associated with observed variation from what was considered by many to be the standard of care. We agree that the role of neoadjuvant chemotherapy in the treatment of advanced ovarian cancer has recently become supported by the aforementioned trial published by Vergote et al. The results of this trial were published in 2010, and as such would not have influenced practice during the study period, and so we did not discuss this trial in this paper examining patterns of care from 1995 to 2005. However, we were also interested in examining outcomes associated with the use of neoadjuvant chemotherapy in the population and have recently published our findings as a separate manuscript [3]. It is interesting to note that in the trial by Vergote et al. which included only patients with extensive stage IIIC and IV ovarian cancers, 88% of patient treated with neoadjuvant chemotherapy were able to undergo surgical debulking, this supporting the notion that the observed 32% in our analysis was surprisingly low. Clearly an aggressive surgical operation and 6 cycles of cytotoxic chemotherapy in any sequence would not be the appropriate care for 100% of elderly women with advanced ovarian cancer. As discussed in our conclusions, many of the patients in our population were likely too ill or may have had progressive disease during treatment that would make “guideline” therapy inappropriate. Or data was limited by an inability to determine with accurate clinical reasons why care was not administered, and as such we refrained from making assumptions or strong conclusions about this based on these data. Despite this limitation, the finding that over 60% of women did not receive the standard of care as defined by the guidelines clearly supports the notion that there is significant room for improvement.
Conflict of interest statement The authors have no conflicts of interest to report.
References [1] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecol Oncol 2011;122:100–6. [2] National Institutes of Health Consensus Development Conference Statement. Ovarian cancer: screening, treatment, and follow-up. Gynecol Oncol 1994;55:S4–S14. [3] Thrall MM, Gray HJ, Symons RG, Weiss NS, Flum DR, Goff BA. Neoadjuvant chemotherapy in the Medicare cohort with advanced ovarian cancer. Gynecol Oncol 2011;123:461–6.
Melissa M. Thrall * Heidi J. Gray Barbara A. Goff Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA, USA ⁎Corresponding author at: University of Washington School of Medicine, Department of Obstetrics and Gynecology Box 356460, Seattle WA 98195-6460, USA. Fax: +1 206 543 3915. E-mail address: [email protected].
doi:10.1016/j.ygyno.2011.12.451
279
Re: “Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multi-institutional phase II trial.” — Proposal of a clinical trial of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced ovarian cancer, the CHORINE study. Keywords: Epithelial ovarian cancer Cytoreductive surgery Hyperthermic intraperitoneal chemotherapy
To the Editor, We read with great interest the article by Deraco et al. [1] reporting the results of a multicenter phase II trial using cytoreductive surgery (CRS) and closed-abdomen hyperthermic intraoperative peritoneal chemotherapy (HIPEC) with cisplatin and doxorubicin in front-line treatment of epithelial ovarian cancer (EOC). The authors accrued 26 patients over 6 years in four different Italian centers, achieving macroscopically complete cytoreduction in 15 patients and only minimal residual disease (≤2.5 mm) in the remaining 11. Although major complications occurred in four patients, including one postoperative death, 25 of the 26 patients started systemic chemotherapy within a median of 46 days after surgery and noticeable five-year overall survival (60.7%) and progression-free survival (15.2%) have been obtained. These results are encouraging and accord with the available literature: nevertheless, in absence of a phase III trial, some considerations should be done before suggesting that CRS+HIPEC could be a valid strategy for upfront treatment of advanced EOC. First, nearly 70% of patients with EOC are diagnosed with advanced stage disease (stage III or IV), due to the non-specific nature of its early symptoms and disease progression. It is well known that primary CRS followed by platinum-based systemic adjuvant chemotherapy, when indicated, is the mainstay of treatment for EOC: in this setting, the aim of primary surgery is to remove as much tumor as possible (possibly all the tumor), because the amount of residual tumor is one of the most important prognostic factors for survival of women with EOC. Although optimal cytoreduction is usually defined as a residual tumor less than 1–2 cm, the evidence from literature is that the achievement of optimal (and better complete) cytoreduction, mainly in advanced EOC, is not always possible, due to extent of disease at time of presentation, medical co-morbidities, and experience of the surgeon [2]. Second, although not performing optimal and complete CRS results in losing the chance for improved survival, it has to be pointed out that radical surgery, especially in very advanced cases, is associated to a high incidence of postoperative morbidity and mortality [3] and could be even increased by the HIPEC procedure [4]. HIPEC remains a burdensome procedure: every effort is needed, before performing this procedure, to select which patients will achieve the maximum benefit from it. Last, it is well known that, although the majority of patients with EOC (up to 80%) respond to first-line platinum based chemotherapy, 20% of them are resistant or refractory. According to these data, the direct administration of high dose HIPEC on residual tumor cells after upfront CRS for advanced EOC would be offered to a certain percentage of women with insensitive chemoresistant tumor cells. Even if not detailed in the article by Deraco et al. [1], the survival curve shows that almost 30% of the patients recurred at one year. It is reasonable to suppose that these patients were not chemo-sensitive patients. HIPEC should be active on chemosensitive cells and the procedure could be avoided in women with insensitive tumor cells. Neoadjuvant chemotherapy (NACT) [5] followed by CRS+HIPEC, valuing the patients' response to NACT, could be a strategy to select for HIPEC only the patients who show chemosensitivity. There are few studies, reported in thirteen papers plus the one of Deraco and colleagues [1] in the literature (the list of these references