- Email: [email protected]
Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis
166
Letters to the Editor
Assessment of nerve sparing surgery is complex and requires a specially designed study with adequate power, not only evaluating the bladder function before and after surgery but also the impact on the bowel and sexual function. This was not within the scope of our paper. The comments on surgical margins seem to be based on a misinterpretation of our data. For clarification, no patient had positive surgical margins, but for some patients the tumor front was less than the 8 mm from the outer margins required for refraining from postoperative chemoradiation in our local treatment protocol. None of the patients were given adjuvant treatment due to insufficient margin towards the vaginal cuff or in the parametria/ paracolpia where the surgeon can affect the radicality of the procedure. Instead “insufficient margins” were all in the anterior/ posterior parts of the cervix where an extended dissection is not possible of obvious anatomical reasons. We certainly have protocols for pathology reports. Moreover, in the article we have in detail described the type of radical hysterectomies performed. The individual numbers of different hysterectomy types does not allow any meaningful comparison. We believe this description and the clarification above sufficiently answer the questions. Concerning Dr Sert's question on a possible inclusion bias we have in detail described the number of women theoretically suitable for radical hysterectomy and the reason why some patients were primarily excluded as well as the number of, and reasons for, conversions (n = 4). The exclusions due to possible intraabdominal adhesions were mainly during the early phase where we had longer operative times. We did not want to add further time to an already long procedure for safety reasons and the risk of severe positioning complications i.e. a compartment syndrome. With increased experience we included also those women. Notably, no woman was converted due to intraabdominal adhesions. Finally, we believe that we have demonstrated the technical feasibility of the method. Dr Sert came to the same conclusion in his series of seven cases referred to in our paper. Conflict of interest statement Jan Persson is a proctor for surgery with the da Vinci robot, no financial support. Thomas Bossmar, Petur Reynisson; no conflicts of interest, no financial support.
Jan Persson⁎ Petur Reynisson Thomas Bossmar Department of Obstetrics and Gynaecology, Lund University Hospital, SE-221 85 Lund, Sweden E-mail address: [email protected]. ⁎Corresponding author. Fax: +46 46157868. 11 June 2009 doi:10.1016/j.ygyno.2009.06.015
Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis To the Editor, Responses to: “Re: Towards randomized trials of peritonectomy and hyperthermic intraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis” and “Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm”. We would like to extend our appreciation to Dr. Markman's important comments on our previous editorial where we proposed
two trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis [1]. In the first trial for primary disease, we plan to randomize patients with primary advanced ovarian cancer to cytoreductive surgery with or without HIPEC. In the second trial for recurrence, we plan to randomize patients who are recurring for the first time after previous treatment (i.e. surgery and chemotherapy or chemotherapy only or surgery only) to cytoreductive surgery with or without HIPEC (Fig. 1). Common between both trials is a cytoreduction which is performed with a maximal effort at extirpating all visible tumor deposits to achieve a complete cytoreduction. In each trial, one arm will receive an intraoperative administration of HIPEC after surgical cytoreduction. Postoperatively, adjuvant systemic chemotherapy using the best available regimen will follow. It is to our belief that current standards in ovarian cancer surgery both for primary disease and for recurrent disease necessitate a surgical effort aimed at a complete cytoreduction. Without doubt, even in the experienced hands of a surgeon with extensive experience in complex abdominal and pelvic cancer surgery, a complete cytoreduction cannot always be achieved due to various reasons, for example, when an overly extensive length of bowel resection is required to achieve complete cytoreduction at an expense of severely compromising postoperative quality of life, a suboptimal cytoreduction would have to be accepted as a maximal effort. Extensive cytoreduction has typically been reported in the surgical oncology literature from numerous specialized treatment centres treating patients with peritoneal surface malignancies. Cytoreductive surgery and HIPEC have yielded promising results in these malignant diseases from which no other systemic therapies have been shown to be beneficial [2–4]. Important to the consideration of this treatment is the evaluation of the perioperative outcomes for which Chua et al. [5] systematically reviewed the morbidity and mortality outcomes of cytoreductive surgery and HIPEC from 10 high volume specialized treatment centres and reported a severe morbidity rate ranging from 12% to 52% and a treatment related mortality rate ranging from 0.9% to 5.8%. This perioperative results is considered acceptable given that no other alternate therapy has been shown to be effective at curing or controlling this disease. In the gynecology oncology literature, eradication of peritoneal deposits from ovarian cancer has been addressed previously by Eisenkop et al. [6], who demonstrated the benefits of peritoneal and serosal implant elimination during primary cytoreductive surgery for patients with advanced ovarian cancer. Subsequent reports from the same group who evaluated their surgical experience in ovarian cancer have consistently supported the need for a complete cytoreduction [7– 9]. However, this notion of a complete cytoreduction was never accepted and has been largely criticized as being an overzealous approach of intervening in patients who had extensive unresectable disease that was a result of poor tumor biology [10,11]. The Gynecology Oncology Group have mandated that optimal cytoreduction in ovarian cancer surgery is defined by residual diseases that are between 1 and 2 cm in sizes. This has been used as a benchmark in recent trials by Alberts et al. [12] and Armstrong et al. [13], who administered intraperitoneal chemotherapy after surgery for patients after cytoreduction of tumors to 2 cm and 1 cm respectively. Today in some tertiary centralized centres caring for ovarian cancer patients, an aggressive approach at cytoreduction has been pursued. This overrides the previous standard staging procedure for ovarian cancer that involved a total hysterectomy, bilateral salphingo-oophorectomy and partial omentectomy to incorporate a more comprehensive initial approach that involved the standard procedures and also extensive upper abdominal resections such as diaphragm peritonectomy, splenectomy, distal pancreatectmomy, partial hepatectomy, cholecystectomy, and portal caval dissection to address tumor deposits in the upper abdomen. Such an approach has been recently reported by Chi et al. [14]. In their experience, they show that
Letters to the Editor
167
Fig. 1. Randomized trials for patients with ovarian cancer peritoneal carcinomatosis (primary advanced ovarian cancer and recurrent ovarian cancer).
since incorporating an aggressive surgical approach to pursue cytoreduction of peritoneal metastases through upper abdominal surgery, there were higher rates of cytoreductions that resulted in residual disease of less than 1 cm (80% vs 46%; p = 0.01) which have led to a superior 5-year progression-free survival of 31% in the group receiving aggressive cytoreduction compared to 14% in the group receiving standard operations (p = 0.01). Overall 5-year survival rates were also superior with the group receiving aggressive cytoreduction (47% vs 35%; p = 0.03). The need for an aggressive surgical approach has also been supported for in two meta-analyses that have demonstrated the survival benefits after maximal cytoreduction [15,16]. We support the conclusions of Chi et al.[14] who encourage a paradigm shift towards more complete primary cytoreduction to improve survival for patients with advanced ovarian, tubal, and peritoneal carcinomas. We believe that our proposed trial will establish standards of surgical care in ovarian cancer and furthermore will elucidate the relative benefits of HIPEC that have been rationalized to aid the process of cytoreduction by targeting microscopic residual disease for which its efficacy has been reported in numerous non-randomized studies [17–20]. We invite interested institutions worldwide to participate in this multi-centre effort to establish evidence based standard of care for patients with ovarian cancer peritoneal carcinomatosis. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] Chua TC, Liauw W, Robertson G, Chia WK, Soo KC, Alobaid A, et al. Towards randomized trials of peritonectomy and hyperthermic intraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis. Gynecol Oncol 2009 Electronic publication. [2] Yan TD, Welch L, Black D, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol 2007;18: 827–34. [3] Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol 2007;14:484–92.
[4] Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol 2006;24:4011–9. [5] Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure? a multiinstitutional review of morbidity and mortality. Ann Surg 2009;249(6):900–7. [6] Eisenkop SM, Nalick RH, Wang HJ, Teng NN. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: impact on survival. Gynecol Oncol 1993;51:224–9. [7] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. [8] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [9] Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with “biological aggressiveness” and survival? Gynecol Oncol 2001;82:435–41. [10] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for ovarian cancer. Obstet Gynecol 1983;61:413–20. [11] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269–74. [12] Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950–5. [13] Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. The Gynecologic Oncology G. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. [14] Chi DS, Eisenhauer EL, Zivanovic O, Sonoda Y, Abu-Rustum NR, Levine DA, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009 Electronic publication. [15] Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009;112:265–74. [16] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [17] Bereder JM. HIPEC in ovarian cancer — French experience. 6th Workshop on Peritoneal Surface Oncology. Lyon; 2008. [18] Di Giorgio A, Naticchioni E, Biacchi D, Sibio S, Accarpio F, Rocco M, et al. Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer 2008;113:315–25. [19] Bae JH, Lee JM, Ryu KS, Lee YS, Park YG, Hur SY, et al. Treatment of ovarian cancer with paclitaxel- or carboplatin-based intraperitoneal hyperthermic chemotherapy during secondary surgery. Gynecol Oncol 2007;106:193–200. [20] Ryu KS, Kim JH, Ko HS, Kim JW, Ahn WS, Park YG, Kim SJ, Lee JM. Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer. Gynecol Oncol 2004;94:325–32.
168
Letters to the Editor
Terence C. Chua University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia Winston Liauw Department of Medical Oncology, St. George Hospital, Sydney, Australia Greg Robertson Department of Gynaecology Oncology, St. George Hospital, Sydney, Australia David L. Morris University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia King Fahad Medical City, Riyadh, Saudi Arabia E-mail address: [email protected]. Corresponding author. University of New South Wales, Department of Surgery, St George Hospital, Kogarah, NSW 2217, Sydney, Australia. Fax: +61 2 9113 3997. 29 May 2009 doi:10.1016/j.ygyno.2009.06.010
Response to: “Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomastis (Chua TC, et al.)”
the treatment are employed [3]. If nothing else, the painful legacy of the history of bone marrow transplantation for breast cancer demonstrates the inherent and major danger associated with a reliance on “evidence” from non-randomized trials (“selection bias”) to support the benefits of an intensive management approach [4,5]. Perhaps a future evidence-based study, as elegant as the two currently proposed by Chu et al., can be initiated that will provide a solid scientific foundation for the aggressive surgery itself [3] Conflict of interest statement No conflict of interest.
References [1] Ozols RF, Locker GY, Doroshow JH, Grotzinger KR, Myers CE, Young RC. Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer. Cancer Res 1979;39(8):3209–14. [2] Los G, Mutsaers PHA, van der Vijgh WJF, Baldew GS, de Graaf PW, McVie JG. Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 1989;49:3380–4. [3] Markman M. Concept of optimal surgical cytoreduction in advanced ovarian cancer: a brief critique and a call for action. J Clin Oncol 2007;25(27):4168–70. [4] Williams SF, Mick R, Desser R, Golick J, Beschorner J, Bitran JD. High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol 1989;7(12):1824–30. [5] Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winer E, et al. Highdose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11(6):1132–43.
Maurie Markman Department of Gynecologic Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA E-mail address: [email protected]. Fax: +1 713 563 9586.
To the Editor, I want to thank Dr. Chua and his colleagues for providing details on their two proposed randomized phase 3 trials that critically examine a potential role for HIPEC (hyperthermic intraperitoneal chemotherapy) in the management of newly diagnosed and recurrent ovarian cancer. The designs are appropriately quite straight-forward, ask a single important question, and (if adequate accrual is accomplished) should provide sorely-needed evidenced-based and clinically-relevant data in this arena. One can easily support the “control arm” of these studies based on the rational statement that if a single delivery of HIPEC is to ever be shown to be of benefit in ovarian cancer it is almost certainly be the case that such benefit will be maximized in patients with essentially no gross macroscopic residual cancer when the treatment is delivered. This is due to the well-established knowledge that the depth of direct drug penetration from the surface of normal or malignant tissue is extremely limited [1,2]. If the trials are negative in this optimal disease setting, the approach will certainly be of no utility in individuals with greater volumes of residual cancer within the peritoneal cavity. Thus, while aggressive surgical cytoreduction alone is clearly the most appropriate control arm to test the utility of HIPEC, and the study results may someday be utilized to support the benefits of combining HIPEC with aggressive surgery (assuming a favorable outcome associated with the “experimental” arm), the assumption that the benefits of aggressive surgery itself (outside the context of these wellconceived clinical trials) have been documented must be seriously questioned. As previously stated, the results of non-randomized studies, and even a meta-analysis of these studies demonstrating the suggested favorable outcome associated with a highly aggressive surgical approach to resect extensive upper abdominal disease may simply demonstrate an outcome based on the wisdom of careful selection and sound clinical judgment (and not intentional bias) in which strategies to offer individual patients rather than a specific effect of
15 June 2009 doi:10.1016/j.ygyno.2009.06.024
In response to: Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis To the Editor, Thank you for the invitation to address the Letter to the Editor entitled “Establishing Evidence for Change in Ovarian Cancer Surgery — Proposing Clinical Trials of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer Peritoneal Carcinomatosis” [1]. In their Letter to the Editor, Chua and colleagues briefly review some of the studies that have supported the modern notion that the goal of primary cytoreductive surgery is to attain a complete gross resection and that a paradigm shift towards this goal (at times utilizing extensive upper abdominal surgical procedures) can lead to significantly improved progression-free and overall survival rates [2–6]. They propose two randomized trials in patients with ovarian cancer. The first trial would randomize patients with advanced ovarian cancer to primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC). In the second trial, patients with their first recurrence would be randomized to secondary cytoreductive surgery with or without HIPEC. We completely agree with Chua et al. that the current standards in ovarian cancer surgery both for primary and recurrent disease necessitate a surgical effort aimed at a complete cytoreduction, but
Letters to the Editor
Assessment of nerve sparing surgery is complex and requires a specially designed study with adequate power, not only evaluating the bladder function before and after surgery but also the impact on the bowel and sexual function. This was not within the scope of our paper. The comments on surgical margins seem to be based on a misinterpretation of our data. For clarification, no patient had positive surgical margins, but for some patients the tumor front was less than the 8 mm from the outer margins required for refraining from postoperative chemoradiation in our local treatment protocol. None of the patients were given adjuvant treatment due to insufficient margin towards the vaginal cuff or in the parametria/ paracolpia where the surgeon can affect the radicality of the procedure. Instead “insufficient margins” were all in the anterior/ posterior parts of the cervix where an extended dissection is not possible of obvious anatomical reasons. We certainly have protocols for pathology reports. Moreover, in the article we have in detail described the type of radical hysterectomies performed. The individual numbers of different hysterectomy types does not allow any meaningful comparison. We believe this description and the clarification above sufficiently answer the questions. Concerning Dr Sert's question on a possible inclusion bias we have in detail described the number of women theoretically suitable for radical hysterectomy and the reason why some patients were primarily excluded as well as the number of, and reasons for, conversions (n = 4). The exclusions due to possible intraabdominal adhesions were mainly during the early phase where we had longer operative times. We did not want to add further time to an already long procedure for safety reasons and the risk of severe positioning complications i.e. a compartment syndrome. With increased experience we included also those women. Notably, no woman was converted due to intraabdominal adhesions. Finally, we believe that we have demonstrated the technical feasibility of the method. Dr Sert came to the same conclusion in his series of seven cases referred to in our paper. Conflict of interest statement Jan Persson is a proctor for surgery with the da Vinci robot, no financial support. Thomas Bossmar, Petur Reynisson; no conflicts of interest, no financial support.
Jan Persson⁎ Petur Reynisson Thomas Bossmar Department of Obstetrics and Gynaecology, Lund University Hospital, SE-221 85 Lund, Sweden E-mail address: [email protected]. ⁎Corresponding author. Fax: +46 46157868. 11 June 2009 doi:10.1016/j.ygyno.2009.06.015
Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis To the Editor, Responses to: “Re: Towards randomized trials of peritonectomy and hyperthermic intraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis” and “Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm”. We would like to extend our appreciation to Dr. Markman's important comments on our previous editorial where we proposed
two trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis [1]. In the first trial for primary disease, we plan to randomize patients with primary advanced ovarian cancer to cytoreductive surgery with or without HIPEC. In the second trial for recurrence, we plan to randomize patients who are recurring for the first time after previous treatment (i.e. surgery and chemotherapy or chemotherapy only or surgery only) to cytoreductive surgery with or without HIPEC (Fig. 1). Common between both trials is a cytoreduction which is performed with a maximal effort at extirpating all visible tumor deposits to achieve a complete cytoreduction. In each trial, one arm will receive an intraoperative administration of HIPEC after surgical cytoreduction. Postoperatively, adjuvant systemic chemotherapy using the best available regimen will follow. It is to our belief that current standards in ovarian cancer surgery both for primary disease and for recurrent disease necessitate a surgical effort aimed at a complete cytoreduction. Without doubt, even in the experienced hands of a surgeon with extensive experience in complex abdominal and pelvic cancer surgery, a complete cytoreduction cannot always be achieved due to various reasons, for example, when an overly extensive length of bowel resection is required to achieve complete cytoreduction at an expense of severely compromising postoperative quality of life, a suboptimal cytoreduction would have to be accepted as a maximal effort. Extensive cytoreduction has typically been reported in the surgical oncology literature from numerous specialized treatment centres treating patients with peritoneal surface malignancies. Cytoreductive surgery and HIPEC have yielded promising results in these malignant diseases from which no other systemic therapies have been shown to be beneficial [2–4]. Important to the consideration of this treatment is the evaluation of the perioperative outcomes for which Chua et al. [5] systematically reviewed the morbidity and mortality outcomes of cytoreductive surgery and HIPEC from 10 high volume specialized treatment centres and reported a severe morbidity rate ranging from 12% to 52% and a treatment related mortality rate ranging from 0.9% to 5.8%. This perioperative results is considered acceptable given that no other alternate therapy has been shown to be effective at curing or controlling this disease. In the gynecology oncology literature, eradication of peritoneal deposits from ovarian cancer has been addressed previously by Eisenkop et al. [6], who demonstrated the benefits of peritoneal and serosal implant elimination during primary cytoreductive surgery for patients with advanced ovarian cancer. Subsequent reports from the same group who evaluated their surgical experience in ovarian cancer have consistently supported the need for a complete cytoreduction [7– 9]. However, this notion of a complete cytoreduction was never accepted and has been largely criticized as being an overzealous approach of intervening in patients who had extensive unresectable disease that was a result of poor tumor biology [10,11]. The Gynecology Oncology Group have mandated that optimal cytoreduction in ovarian cancer surgery is defined by residual diseases that are between 1 and 2 cm in sizes. This has been used as a benchmark in recent trials by Alberts et al. [12] and Armstrong et al. [13], who administered intraperitoneal chemotherapy after surgery for patients after cytoreduction of tumors to 2 cm and 1 cm respectively. Today in some tertiary centralized centres caring for ovarian cancer patients, an aggressive approach at cytoreduction has been pursued. This overrides the previous standard staging procedure for ovarian cancer that involved a total hysterectomy, bilateral salphingo-oophorectomy and partial omentectomy to incorporate a more comprehensive initial approach that involved the standard procedures and also extensive upper abdominal resections such as diaphragm peritonectomy, splenectomy, distal pancreatectmomy, partial hepatectomy, cholecystectomy, and portal caval dissection to address tumor deposits in the upper abdomen. Such an approach has been recently reported by Chi et al. [14]. In their experience, they show that
Letters to the Editor
167
Fig. 1. Randomized trials for patients with ovarian cancer peritoneal carcinomatosis (primary advanced ovarian cancer and recurrent ovarian cancer).
since incorporating an aggressive surgical approach to pursue cytoreduction of peritoneal metastases through upper abdominal surgery, there were higher rates of cytoreductions that resulted in residual disease of less than 1 cm (80% vs 46%; p = 0.01) which have led to a superior 5-year progression-free survival of 31% in the group receiving aggressive cytoreduction compared to 14% in the group receiving standard operations (p = 0.01). Overall 5-year survival rates were also superior with the group receiving aggressive cytoreduction (47% vs 35%; p = 0.03). The need for an aggressive surgical approach has also been supported for in two meta-analyses that have demonstrated the survival benefits after maximal cytoreduction [15,16]. We support the conclusions of Chi et al.[14] who encourage a paradigm shift towards more complete primary cytoreduction to improve survival for patients with advanced ovarian, tubal, and peritoneal carcinomas. We believe that our proposed trial will establish standards of surgical care in ovarian cancer and furthermore will elucidate the relative benefits of HIPEC that have been rationalized to aid the process of cytoreduction by targeting microscopic residual disease for which its efficacy has been reported in numerous non-randomized studies [17–20]. We invite interested institutions worldwide to participate in this multi-centre effort to establish evidence based standard of care for patients with ovarian cancer peritoneal carcinomatosis. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] Chua TC, Liauw W, Robertson G, Chia WK, Soo KC, Alobaid A, et al. Towards randomized trials of peritonectomy and hyperthermic intraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis. Gynecol Oncol 2009 Electronic publication. [2] Yan TD, Welch L, Black D, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol 2007;18: 827–34. [3] Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol 2007;14:484–92.
[4] Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol 2006;24:4011–9. [5] Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure? a multiinstitutional review of morbidity and mortality. Ann Surg 2009;249(6):900–7. [6] Eisenkop SM, Nalick RH, Wang HJ, Teng NN. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: impact on survival. Gynecol Oncol 1993;51:224–9. [7] Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. [8] Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998;69:103–8. [9] Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with “biological aggressiveness” and survival? Gynecol Oncol 2001;82:435–41. [10] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for ovarian cancer. Obstet Gynecol 1983;61:413–20. [11] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269–74. [12] Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950–5. [13] Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. The Gynecologic Oncology G. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. [14] Chi DS, Eisenhauer EL, Zivanovic O, Sonoda Y, Abu-Rustum NR, Levine DA, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009 Electronic publication. [15] Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009;112:265–74. [16] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [17] Bereder JM. HIPEC in ovarian cancer — French experience. 6th Workshop on Peritoneal Surface Oncology. Lyon; 2008. [18] Di Giorgio A, Naticchioni E, Biacchi D, Sibio S, Accarpio F, Rocco M, et al. Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer 2008;113:315–25. [19] Bae JH, Lee JM, Ryu KS, Lee YS, Park YG, Hur SY, et al. Treatment of ovarian cancer with paclitaxel- or carboplatin-based intraperitoneal hyperthermic chemotherapy during secondary surgery. Gynecol Oncol 2007;106:193–200. [20] Ryu KS, Kim JH, Ko HS, Kim JW, Ahn WS, Park YG, Kim SJ, Lee JM. Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer. Gynecol Oncol 2004;94:325–32.
168
Letters to the Editor
Terence C. Chua University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia Winston Liauw Department of Medical Oncology, St. George Hospital, Sydney, Australia Greg Robertson Department of Gynaecology Oncology, St. George Hospital, Sydney, Australia David L. Morris University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia King Fahad Medical City, Riyadh, Saudi Arabia E-mail address: [email protected]. Corresponding author. University of New South Wales, Department of Surgery, St George Hospital, Kogarah, NSW 2217, Sydney, Australia. Fax: +61 2 9113 3997. 29 May 2009 doi:10.1016/j.ygyno.2009.06.010
Response to: “Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomastis (Chua TC, et al.)”
the treatment are employed [3]. If nothing else, the painful legacy of the history of bone marrow transplantation for breast cancer demonstrates the inherent and major danger associated with a reliance on “evidence” from non-randomized trials (“selection bias”) to support the benefits of an intensive management approach [4,5]. Perhaps a future evidence-based study, as elegant as the two currently proposed by Chu et al., can be initiated that will provide a solid scientific foundation for the aggressive surgery itself [3] Conflict of interest statement No conflict of interest.
References [1] Ozols RF, Locker GY, Doroshow JH, Grotzinger KR, Myers CE, Young RC. Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer. Cancer Res 1979;39(8):3209–14. [2] Los G, Mutsaers PHA, van der Vijgh WJF, Baldew GS, de Graaf PW, McVie JG. Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 1989;49:3380–4. [3] Markman M. Concept of optimal surgical cytoreduction in advanced ovarian cancer: a brief critique and a call for action. J Clin Oncol 2007;25(27):4168–70. [4] Williams SF, Mick R, Desser R, Golick J, Beschorner J, Bitran JD. High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol 1989;7(12):1824–30. [5] Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winer E, et al. Highdose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11(6):1132–43.
Maurie Markman Department of Gynecologic Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA E-mail address: [email protected]. Fax: +1 713 563 9586.
To the Editor, I want to thank Dr. Chua and his colleagues for providing details on their two proposed randomized phase 3 trials that critically examine a potential role for HIPEC (hyperthermic intraperitoneal chemotherapy) in the management of newly diagnosed and recurrent ovarian cancer. The designs are appropriately quite straight-forward, ask a single important question, and (if adequate accrual is accomplished) should provide sorely-needed evidenced-based and clinically-relevant data in this arena. One can easily support the “control arm” of these studies based on the rational statement that if a single delivery of HIPEC is to ever be shown to be of benefit in ovarian cancer it is almost certainly be the case that such benefit will be maximized in patients with essentially no gross macroscopic residual cancer when the treatment is delivered. This is due to the well-established knowledge that the depth of direct drug penetration from the surface of normal or malignant tissue is extremely limited [1,2]. If the trials are negative in this optimal disease setting, the approach will certainly be of no utility in individuals with greater volumes of residual cancer within the peritoneal cavity. Thus, while aggressive surgical cytoreduction alone is clearly the most appropriate control arm to test the utility of HIPEC, and the study results may someday be utilized to support the benefits of combining HIPEC with aggressive surgery (assuming a favorable outcome associated with the “experimental” arm), the assumption that the benefits of aggressive surgery itself (outside the context of these wellconceived clinical trials) have been documented must be seriously questioned. As previously stated, the results of non-randomized studies, and even a meta-analysis of these studies demonstrating the suggested favorable outcome associated with a highly aggressive surgical approach to resect extensive upper abdominal disease may simply demonstrate an outcome based on the wisdom of careful selection and sound clinical judgment (and not intentional bias) in which strategies to offer individual patients rather than a specific effect of
15 June 2009 doi:10.1016/j.ygyno.2009.06.024
In response to: Establishing evidence for change in ovarian cancer surgery — Proposing clinical trials of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer peritoneal carcinomatosis To the Editor, Thank you for the invitation to address the Letter to the Editor entitled “Establishing Evidence for Change in Ovarian Cancer Surgery — Proposing Clinical Trials of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer Peritoneal Carcinomatosis” [1]. In their Letter to the Editor, Chua and colleagues briefly review some of the studies that have supported the modern notion that the goal of primary cytoreductive surgery is to attain a complete gross resection and that a paradigm shift towards this goal (at times utilizing extensive upper abdominal surgical procedures) can lead to significantly improved progression-free and overall survival rates [2–6]. They propose two randomized trials in patients with ovarian cancer. The first trial would randomize patients with advanced ovarian cancer to primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC). In the second trial, patients with their first recurrence would be randomized to secondary cytoreductive surgery with or without HIPEC. We completely agree with Chua et al. that the current standards in ovarian cancer surgery both for primary and recurrent disease necessitate a surgical effort aimed at a complete cytoreduction, but