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Cytoreductive surgery for advanced ovarian cancer Martin Pölcher*1, Oliver Zivanovic2 & Dennis S Chi2 The amount of the largest diameter of visible residual tumor after cytoreductive surgery remains one of the strongest prognostic factors in advanced ovarian cancer. The implementation of a more aggressive surgical approach to increase the proportion of patients without visible residual tumor is, therefore, a rational concept. Thus, the surgical management of advanced ovarian, primary peritoneal and fallopian tube cancers now incorporates more comprehensive surgical procedures. However, these more extensive surgical procedures are associated with an increased risk of morbidity, which may have a negative impact on the oncologic outcome. In addition, it is unclear whether all patients benefit from a comprehensive surgical intervention in the same way or if there are patients whose disease course will not be influenced by this approach. The methodologic analysis of surgical effectiveness is complex and controversial owing to a lack of prospective surgical trials. This review acknowledges controversies and aims to discuss novel developments in the field of cytoreductive surgery for patients with ovarian, primary peritoneal and fallopian tube cancers. The focus of the review is to discuss the role of surgery at initial diagnosis. The role of secondary and tertiary surgery in the recurrent setting is beyond the scope of this review.
Ovarian, primary peritoneal and fallopian tube cancers are the most lethal gynecologic malignancies, with 22,280 estimated new cases and 15,500 estimated deaths in 2012 in the USA [1]. The majority of patients (60–70%) present at an advanced disease stage at the time of initial diagnosis with overt peritoneal extrapelvic disease, lymph node involvement or distant metastatic disease beyond the peritoneal cavity and parenchymal liver metastasis (International Federation of Gynecology and Obstetrics [FIGO] stage III and IV, respectively) [1,2]. The natural history of advanced ovarian cancer is one of clinical remission after primary cytoreductive surgery (CRS) and postoperative chemo t herapy; however, the majority of patients recur within 24 months and long-term cure rates languish between 20 and 30%. Positive results from different improvement strategies have been reported over the past few years. Modification of the medical treatment after surgery demonstrated a benefit for patients treated with dose-dense intravenous (iv.) chemot herapy [3], for patients who underwent a combination of intraperitoneal (ip.) and iv. treatment [4], and for patients who were treated with a maintenance antiangiogenetic therapy after chemotherapy (mono c lonal anti-VEGF antibody, bevacizumab, or oral angiogenesis inhibitor, pazopanib [5–7]). Riskreducing strategies, for example, prophylactic salpingo-oophorectomy, reduce mortality in a 10.2217/WHE.14.4 © 2014 Future Medicine Ltd
high-risk population with germline mutations (BRCA1/2) [8]. However, effective screening strategies to detect early-stage diseases have not been established and continue to be elusive. Role of surgery
In contrast to other solid malignancies of the upper abdomen (e.g., pancreas, gallbladder and stomach), ovarian, primary peritoneal and fallopian tube carcinomas are sensitive to platinum-based combination chemotherapy in up to 80% of cases. The distinct chemosensitivity justifies a more extensive surgical approach. Surgical cytoreduction of advanced stage ovarian cancer, also termed ‘tumor debulking’, is defined as an attempt to maximally resect all visible and palpable disease. Postoperative residual disease is a variable of great importance for estimating the prognosis and guiding further treatment of affected patients. Radical surgical approach for advanced ovarian carcinoma
The term ‘radical surgery’ used for cancer surgery was introduced by William Halsted at the beginning of the 20th century and originates from the word radix, for example, removing the cancerous lesion including the root (radix) with tumor-free microscopic margins. In analogy, William Halsted surgically removed the entire breast, including the underlying muscle and the axillary lymph nodes to reduce the risk of Women's Health (2014) 10(2), 179–190
Red Cross Women’s Hospital Munich, Department of Gynecologic Oncology & Minimally-Invasive Surgery, Munich, Germany 2 Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Author for correspondence: [email protected] 1
Keywords • advanced ovarian carcinoma • cytoreductive surgery • hyperthermic intraoperative intraperitoneal chemotherapy
part of
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Review – Pölcher, Zivanovic & Chi local recurrence in patients with breast cancer. It was not until the late 1970s that Bernhard Fisher was able to prove equivalent outcomes for patients treated with less radical breastconserving surgery followed by local radiation therapy in patients with breast cancer. Unlike breast cancer, ovarian cancer involves the peritoneal surface with diffuse peritoneal carcinomatosis and the goal of CRS is to resect all macroscopic tumor lesions, not to remove the tumor with a tumor-free microscopic margin status. The goal of surgical cytoreduction of advanced stage ovarian cancer is to maximally resect all visible and palpable disease. There is a large body of evidence that demonstrates a survival benefit for patients who are left with minimal (‘optimally cytoreduced’) disease after surgery. For more than 30 years, it has been known that women with advanced ovarian cancer, who are left with an apparent small volume of residual disease following primary surgery and go on to receive systemic chemot herapy, have a superior outcome compared with patients who are left with a larger volume disease after initial surgery. In 1934, Meigs suggested removing as much tumor as possible to enhance the effectiveness of postoperative radiation therapy in patients with advanced ovarian cancer [9]. The radicality of this surgical approach is not related to the resection of predefined anatomic compartments but, rather, is based on multiple procedures individually targeting the organs involved with disease with the goal to achieve ‘optimal debulking’ status. These procedures include, but are not limited to, hysterectomy and salpingooophorectomy, peritonectomy with or without gastrointestinal surgery, lymph node dissection, omentectomy and upper abdominal surgery. In 1975, Griffiths hypothesized a thres hold – a maximum tumor diameter – that may remain after CRS independent of the number of tumor lesions without compromising the benefit of the surgical procedure [10]. Hoskins et al. were able to confirm this hypothesis [11]. Thus, patients who undergo suboptimal cytoreduction sustain the morbidity of a cytoreductive attempt without the associated survival benefit. Consequently, the Gynecologic Oncology Group defined a maximum tumor diameter of 1 cm or less as an optimal surgical outcome strongly associated with survival. In addition, multiple retrospective studies and meta-analyses have demonstrated and confirmed that the amount of residual disease after CRS inversely correlates with progression-free 180
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and overall survival (OS), and that increasing optimal cytoreduction rates with more extensive and complex surgical efforts is associated with improved outcomes [12–18]. Prognostic impact of postoperative residual disease
Although, to date, the benefit of surgical cytoreduction has not been prospectively established through a well-defined prospective Phase III trial, CRS with the goal of achieving minimal residual disease in combination with platinum- and taxane-based chemotherapy is currently the accepted standard management. However, in the absence of prospective trials, we cannot say for sure whether the surgery itself is responsible for the superior outcome associated with small-volume residual disease or whether these patients are part of a biologically more favorable subgroup with excellent response to postoperative chemotherapy. The evidence strongly supporting the role of surgery has been derived from different types of ana lysis. Single-center studies
A retrospective analysis of 465 patients at Memorial Sloan-Kettering Cancer Center (NY, USA) with ‘bulky’ FIGO stage IIIC disease (those stage IIIC patients with nodal involvement only were excluded) revealed three distinct groups with significantly different survival rates (p 1 cm [13]. Although the difference in survival in patients left with smaller volume ≤1 cm was significant when compared with those with suboptimal residual disease, there was a trend in patients with gross up to 0.5 cm residual compared with those with 0.6 cm up to 1 cm (p = 0.06), suggesting that each incremental decrease in residual tumor below 1 cm may be associated with an incremental improvement in OS. Aletti et al. analyzed a patient cohort of 194 patients, including 144 with peritoneal carcinomatosis [12]. The only independent predictor of survival was residual disease of 1 cm, radical surgery in the abdominal cavity is debatable. Conclusion
The natural history of advanced ovarian cancer is one of clinical remission after primary CRS and postoperative chemotherapy; however, the majority of patients recur within 24 months, and longterm cure rates languish between 20 and 30%. Since the amount of the largest diameter of visible residual tumor after CRS remains one of the strongest prognostic factors, an aggressive surgical approach is taken to increase the proportion of patients without visible residual tumor. However, more extensive surgical procedures are associated with an increased risk of morbidity, which may have a negative impact on the oncologic outcome. One promising new treatment strategy is to combine surgical cytoreduction with hyperthermic intraoperative ip. chemotherapy (HIPEC). future science group
Cytoreductive surgery for advanced ovarian cancer –
Further study of HIPEC, and development of additional treatment strategies, are needed. Future perspective: the role of HIPEC
Since EOC remains confined to the peritoneal cavity for most of its natural history, numerous theoretical studies evaluated the use of ip. drug delivery as a management strategy [72–74]. The studies predicted a pharmacologic advantage for ip. therapy with improved tumor cell access, longer half-life in the peritoneal compartment, increased dose intensity and slow peritoneal clearance, while still reaching sufficient levels of systemic exposure for longer periods of time. Further preclinical data for platinum agents revealed that resistence to the drugs can be overcome by exposing the tumor cells to higher ip. concentrations. Animal studies confirmed that the peritoneal cavity can be exposed to substantially greater concentrations of cytotoxic
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agents [75–77]. Owing to the production of severe side effects, these concentrations are not realistically attainable within the systemic compartment. Based on these data, several Phase III clinical trials have explored the clinical utility of postoperative ip. therapy of small-volume residual disease following maximal CRS of advanced EOC [4,78,79]. In these trials, after postoperative recovery cisplatin-based ip. therapy was delivered through an ip. access device and compared with standard iv. chemotherapy. In the most recent of these trials (GOG-172), there was a statistically significant increase in the median PFS and OS in the cisplatin/paclitaxel ip. treatment compared with the iv. group, with a benefit of 6 and 16 months, respectively. These findings have prompted the National Cancer Institute (MD, USA) to make a clinical announcement in 2006; since then, postoperative ip. treatment in patients with minimal residual disease after
Table 2. Ongoing studies evaluating the role of hyperthermic intraperitoneal chemotherapy for patients with ovarian cancer. Disease status (trial design)
ClinicalTrials. Study gov identifier
Platinum-sensitive recurrence NCT01539785 (randomized)
Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence (HORSE)
Primary stage III or only NCT01709487 pleural stage IV ovarian carcinoma after neoadjuvant chemotherapy (nonrandomized)
Feasibility Study of HIPEC for Patients With Stage III or Only Pleural Stage IV Ovarian Carcinoma in First Line Therapy
Primary epithelial ovarian/ NCT01628380 tubal (FIGO stage IIIC) with complete or partial clinical response after three cycles of neoadjuvant chemotherapy (randomized)
Phase 3 Trial Evaluating Hyperthermic Intraperitoneal Chemotherapy in Upfront Treatment of Stage IIIC Epithelial Ovarian Cancer (CHORINE)
FIGO stage III ovarian cancer after primary/ neoadjuvant chemotherapy (randomized)
Interval debulking Surgery ± Hyperthermic Intraperitoneal Chemotherapy in Stage III Ovarian Cancer
NCT00426257
Platinum-sensitive recurrence NCT01767675 (randomized)
Outcomes After Secondary Cytoreductive Surgery With or Without Carboplatin Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Followed by Systemic Combination Chemotherapy for Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Recurrent ovarian, primary NCT01659554 peritoneal and fallopian tube carcinomas (nonrandomized)
A Phase II Combined Modality Protocol of Debulking Surgery With HIPEC Followed by Intraperitoneal Chemotherapy for the Treatment of Recurrent Ovarian, Primary Peritoneal & Fallopian Tube Cancers
Recurrent ovarian cancer after second-line chemotherapy (randomized)
Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) in Relapse Ovarian Cancer Treatment (CHIPOR)
NCT01376752
FIGO: International Federation of Gynecology and Obstetrics.
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Review – Pölcher, Zivanovic & Chi surgical cytoreduction is increasingly used in the USA and continues to be the subject of ongoing randomized trials with new regimens and new/additional drugs [80]. However, a substantial percentage of the patients (60%) were unable to complete six cycles of cisplatin/paclitaxel ip. chemotherapy, most commonly secondary to abdominal discomfort due to postoperative adhesion barriers and ip. catheter-related complications. Therefore, the European Organization for Research and Treatment of Cancer (Brussels, Belgium) and other international organizations are still unconvinced by available data and still consider this treatment experimental [81]. However, despite only 48% of the patients receiving three or fewer cycles of ip. therapy, the ip. group had significant improvement in median survival compared with the iv. group. An alternative to the postoperative local drug delivery is the intraoperative chemotherapy. For several reasons, there has been increasing interest in the surgical oncology community for combining surgical cytoreduction and hyperthermic ip. drug delivery (HIPEC) in the management of solid tumors whose natural history remains principally localized to the peritoneal cavity. The advantages are as follows: • By giving the chemotherapy intraoperatively, drug exposure is optimal secondary to direct contact with the cancer cells without the barriers of postoperative adhesions;
• Intraoperatively, the chemotherapy can be delivered under highly standardized procedures and the surgeon can guarantee optimal distribution of the chemotherapy, and dwell times can be controlled; • Hyperthermia has been shown to increase the cytotoxic effect of many chemotherapeutic agents by increasing DNA-crosslinking and increasing the tumor penetration [82–84]. A comprehensive review of HIPEC is beyond the scope of this review, but such publications are available [85–92]. This approach has been explored in the treatment of patients with peritoneal malignancies, including pseudomyxoma peritonei, gastric cancer and colorectal malignancies, suggesting a survival benefit using this approach. Unfortunately, there is essentially no evidence from prospective trials to objectively confirm any claimed benefits associated with this approach for patients with advanced EOC. The existing studies on HIPEC are mostly retrospective in nature, heterogeneous with regards to combined inclusion of primary and recurrent disease, and lack robust dose-finding and pharmacok inetic data. Until evidencebased trials yield further data, it is reasonable to conclude that surgical cytoreduction with HIPEC offers a rational, but still investigative, approach in the management of EOC, the use of which should be employed under
Executive summary Background • Ovarian, primary peritoneal and fallopian tube cancers are the most lethal gynecologic malignancies. Prognostic impact of postoperative residual disease • Retrospective studies and meta-analyses have demonstrated and confirmed that the amount of residual disease after cytoreductive surgery (CRS) inversely correlates with progression-free and overall survival. • Increasing optimal cytoreduction rates with more extensive and complex surgical efforts is associated with improved outcomes. Obtaining a higher rate of primary optimal cytoreduction • Advances in surgical training, technique and perioperative care have allowed surgeons to maximize cytoreductive efforts, enabling them to increase the rate of optimal cytoreduction. The role of neoadjuvant chemotherapy • The rate of patients with no gross residual tumor was significantly higher after neoadjuvant chemotherapy when compared with patients who underwent primary CRS. However, the increase in complete gross resection rates after neoadjuvant chemotherapy does not translate into improved outcomes observed in patients who undergo primary CRS. Risks associated with surgical cytoreduction • Surgical cytoreduction is associated with a risk of morbidity and mortality. Single center data quantified the mortality rate after CRS in advanced ovarian cancer to be between 1.4 and 2.5%. • Risk factors for higher mortality in these studies are age, performance status and comorbidities, as well as emergency treatment compared with patients who were treated electively. Video-assisted thoracoscopic surgery • Patients with pleural effusions may benefit from a video-assisted thoracoscopic surgery for diagnosis and intrathoracic cytoreduction. Hyperthermic intraperitoneal drug delivery • Combining surgical cytoreduction and hyperthermic intraperitoneal drug delivery is a rational, but still investigative, approach in the management of epithelial ovarian cancer.
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the umbrella of Institutional Review Boardapproved clinical trials. One randomized Phase II trial has been initiated recently at the Memorial Sloan-Kettering Cancer Center [93]. This is a randomized trial designed to compare the efficacy and safety of carboplatin at a dose of 800 mg/m2 administered as HIPEC after secondary CRS for recurrent platinum-sensitive EOC. Patients with minimal residual disease of 5 mm or less will be randomized 1:1 to CRS with HIPEC (arm A; n = 49) or CRS only (arm B; n = 49). Both arms will receive standard postoperative iv. chemotherapy. The primary objective is to determine the proportion of patients who are without evidence of Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
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Katsumata N, Yasuda M, Takahashi F et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a Phase 3, open-label, randomised controlled trial. Lancet 374(9698), 1331–1338 (2009). Armstrong DK, Bundy B, Wenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 354(1), 34–43 (2006). These findings prompted the National Cancer Institute (MD, USA) to make a clinical announcement in 2006. Based on the results of these randomized Phase III trials, a combination of intravenous and intraperitoneal administration of chemotherapy conveys a significant survival benefit among women with optimally debulked epithelial ovarian cancer compared with intravenous administration alone. Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365(26), 2473–2483 (2011). Perren TJ, Swart AM, Pfisterer J et al. A Phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365(26), 2484–2496 (2011). Du Bois A, Floquet A, Kim JW et al. Randomized, double-blind, Phase III trial of
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disease progression at 24 months after CRS with or without HIPEC. Current ongoing clinical trials are listed in Table 2 . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international intergroup trial (AGO-OVAR16) J. Clin. Oncol. (Suppl.), Abstract LBA5503 (2013).
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Cytoreductive surgery for advanced ovarian cancer Martin Pölcher*1, Oliver Zivanovic2 & Dennis S Chi2 The amount of the largest diameter of visible residual tumor after cytoreductive surgery remains one of the strongest prognostic factors in advanced ovarian cancer. The implementation of a more aggressive surgical approach to increase the proportion of patients without visible residual tumor is, therefore, a rational concept. Thus, the surgical management of advanced ovarian, primary peritoneal and fallopian tube cancers now incorporates more comprehensive surgical procedures. However, these more extensive surgical procedures are associated with an increased risk of morbidity, which may have a negative impact on the oncologic outcome. In addition, it is unclear whether all patients benefit from a comprehensive surgical intervention in the same way or if there are patients whose disease course will not be influenced by this approach. The methodologic analysis of surgical effectiveness is complex and controversial owing to a lack of prospective surgical trials. This review acknowledges controversies and aims to discuss novel developments in the field of cytoreductive surgery for patients with ovarian, primary peritoneal and fallopian tube cancers. The focus of the review is to discuss the role of surgery at initial diagnosis. The role of secondary and tertiary surgery in the recurrent setting is beyond the scope of this review.
Ovarian, primary peritoneal and fallopian tube cancers are the most lethal gynecologic malignancies, with 22,280 estimated new cases and 15,500 estimated deaths in 2012 in the USA [1]. The majority of patients (60–70%) present at an advanced disease stage at the time of initial diagnosis with overt peritoneal extrapelvic disease, lymph node involvement or distant metastatic disease beyond the peritoneal cavity and parenchymal liver metastasis (International Federation of Gynecology and Obstetrics [FIGO] stage III and IV, respectively) [1,2]. The natural history of advanced ovarian cancer is one of clinical remission after primary cytoreductive surgery (CRS) and postoperative chemo t herapy; however, the majority of patients recur within 24 months and long-term cure rates languish between 20 and 30%. Positive results from different improvement strategies have been reported over the past few years. Modification of the medical treatment after surgery demonstrated a benefit for patients treated with dose-dense intravenous (iv.) chemot herapy [3], for patients who underwent a combination of intraperitoneal (ip.) and iv. treatment [4], and for patients who were treated with a maintenance antiangiogenetic therapy after chemotherapy (mono c lonal anti-VEGF antibody, bevacizumab, or oral angiogenesis inhibitor, pazopanib [5–7]). Riskreducing strategies, for example, prophylactic salpingo-oophorectomy, reduce mortality in a 10.2217/WHE.14.4 © 2014 Future Medicine Ltd
high-risk population with germline mutations (BRCA1/2) [8]. However, effective screening strategies to detect early-stage diseases have not been established and continue to be elusive. Role of surgery
In contrast to other solid malignancies of the upper abdomen (e.g., pancreas, gallbladder and stomach), ovarian, primary peritoneal and fallopian tube carcinomas are sensitive to platinum-based combination chemotherapy in up to 80% of cases. The distinct chemosensitivity justifies a more extensive surgical approach. Surgical cytoreduction of advanced stage ovarian cancer, also termed ‘tumor debulking’, is defined as an attempt to maximally resect all visible and palpable disease. Postoperative residual disease is a variable of great importance for estimating the prognosis and guiding further treatment of affected patients. Radical surgical approach for advanced ovarian carcinoma
The term ‘radical surgery’ used for cancer surgery was introduced by William Halsted at the beginning of the 20th century and originates from the word radix, for example, removing the cancerous lesion including the root (radix) with tumor-free microscopic margins. In analogy, William Halsted surgically removed the entire breast, including the underlying muscle and the axillary lymph nodes to reduce the risk of Women's Health (2014) 10(2), 179–190
Red Cross Women’s Hospital Munich, Department of Gynecologic Oncology & Minimally-Invasive Surgery, Munich, Germany 2 Department of Surgery, Gynecology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Author for correspondence: [email protected] 1
Keywords • advanced ovarian carcinoma • cytoreductive surgery • hyperthermic intraoperative intraperitoneal chemotherapy
part of
ISSN 1745-5057
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Review – Pölcher, Zivanovic & Chi local recurrence in patients with breast cancer. It was not until the late 1970s that Bernhard Fisher was able to prove equivalent outcomes for patients treated with less radical breastconserving surgery followed by local radiation therapy in patients with breast cancer. Unlike breast cancer, ovarian cancer involves the peritoneal surface with diffuse peritoneal carcinomatosis and the goal of CRS is to resect all macroscopic tumor lesions, not to remove the tumor with a tumor-free microscopic margin status. The goal of surgical cytoreduction of advanced stage ovarian cancer is to maximally resect all visible and palpable disease. There is a large body of evidence that demonstrates a survival benefit for patients who are left with minimal (‘optimally cytoreduced’) disease after surgery. For more than 30 years, it has been known that women with advanced ovarian cancer, who are left with an apparent small volume of residual disease following primary surgery and go on to receive systemic chemot herapy, have a superior outcome compared with patients who are left with a larger volume disease after initial surgery. In 1934, Meigs suggested removing as much tumor as possible to enhance the effectiveness of postoperative radiation therapy in patients with advanced ovarian cancer [9]. The radicality of this surgical approach is not related to the resection of predefined anatomic compartments but, rather, is based on multiple procedures individually targeting the organs involved with disease with the goal to achieve ‘optimal debulking’ status. These procedures include, but are not limited to, hysterectomy and salpingooophorectomy, peritonectomy with or without gastrointestinal surgery, lymph node dissection, omentectomy and upper abdominal surgery. In 1975, Griffiths hypothesized a thres hold – a maximum tumor diameter – that may remain after CRS independent of the number of tumor lesions without compromising the benefit of the surgical procedure [10]. Hoskins et al. were able to confirm this hypothesis [11]. Thus, patients who undergo suboptimal cytoreduction sustain the morbidity of a cytoreductive attempt without the associated survival benefit. Consequently, the Gynecologic Oncology Group defined a maximum tumor diameter of 1 cm or less as an optimal surgical outcome strongly associated with survival. In addition, multiple retrospective studies and meta-analyses have demonstrated and confirmed that the amount of residual disease after CRS inversely correlates with progression-free 180
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and overall survival (OS), and that increasing optimal cytoreduction rates with more extensive and complex surgical efforts is associated with improved outcomes [12–18]. Prognostic impact of postoperative residual disease
Although, to date, the benefit of surgical cytoreduction has not been prospectively established through a well-defined prospective Phase III trial, CRS with the goal of achieving minimal residual disease in combination with platinum- and taxane-based chemotherapy is currently the accepted standard management. However, in the absence of prospective trials, we cannot say for sure whether the surgery itself is responsible for the superior outcome associated with small-volume residual disease or whether these patients are part of a biologically more favorable subgroup with excellent response to postoperative chemotherapy. The evidence strongly supporting the role of surgery has been derived from different types of ana lysis. Single-center studies
A retrospective analysis of 465 patients at Memorial Sloan-Kettering Cancer Center (NY, USA) with ‘bulky’ FIGO stage IIIC disease (those stage IIIC patients with nodal involvement only were excluded) revealed three distinct groups with significantly different survival rates (p 1 cm [13]. Although the difference in survival in patients left with smaller volume ≤1 cm was significant when compared with those with suboptimal residual disease, there was a trend in patients with gross up to 0.5 cm residual compared with those with 0.6 cm up to 1 cm (p = 0.06), suggesting that each incremental decrease in residual tumor below 1 cm may be associated with an incremental improvement in OS. Aletti et al. analyzed a patient cohort of 194 patients, including 144 with peritoneal carcinomatosis [12]. The only independent predictor of survival was residual disease of 1 cm, radical surgery in the abdominal cavity is debatable. Conclusion
The natural history of advanced ovarian cancer is one of clinical remission after primary CRS and postoperative chemotherapy; however, the majority of patients recur within 24 months, and longterm cure rates languish between 20 and 30%. Since the amount of the largest diameter of visible residual tumor after CRS remains one of the strongest prognostic factors, an aggressive surgical approach is taken to increase the proportion of patients without visible residual tumor. However, more extensive surgical procedures are associated with an increased risk of morbidity, which may have a negative impact on the oncologic outcome. One promising new treatment strategy is to combine surgical cytoreduction with hyperthermic intraoperative ip. chemotherapy (HIPEC). future science group
Cytoreductive surgery for advanced ovarian cancer –
Further study of HIPEC, and development of additional treatment strategies, are needed. Future perspective: the role of HIPEC
Since EOC remains confined to the peritoneal cavity for most of its natural history, numerous theoretical studies evaluated the use of ip. drug delivery as a management strategy [72–74]. The studies predicted a pharmacologic advantage for ip. therapy with improved tumor cell access, longer half-life in the peritoneal compartment, increased dose intensity and slow peritoneal clearance, while still reaching sufficient levels of systemic exposure for longer periods of time. Further preclinical data for platinum agents revealed that resistence to the drugs can be overcome by exposing the tumor cells to higher ip. concentrations. Animal studies confirmed that the peritoneal cavity can be exposed to substantially greater concentrations of cytotoxic
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agents [75–77]. Owing to the production of severe side effects, these concentrations are not realistically attainable within the systemic compartment. Based on these data, several Phase III clinical trials have explored the clinical utility of postoperative ip. therapy of small-volume residual disease following maximal CRS of advanced EOC [4,78,79]. In these trials, after postoperative recovery cisplatin-based ip. therapy was delivered through an ip. access device and compared with standard iv. chemotherapy. In the most recent of these trials (GOG-172), there was a statistically significant increase in the median PFS and OS in the cisplatin/paclitaxel ip. treatment compared with the iv. group, with a benefit of 6 and 16 months, respectively. These findings have prompted the National Cancer Institute (MD, USA) to make a clinical announcement in 2006; since then, postoperative ip. treatment in patients with minimal residual disease after
Table 2. Ongoing studies evaluating the role of hyperthermic intraperitoneal chemotherapy for patients with ovarian cancer. Disease status (trial design)
ClinicalTrials. Study gov identifier
Platinum-sensitive recurrence NCT01539785 (randomized)
Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence (HORSE)
Primary stage III or only NCT01709487 pleural stage IV ovarian carcinoma after neoadjuvant chemotherapy (nonrandomized)
Feasibility Study of HIPEC for Patients With Stage III or Only Pleural Stage IV Ovarian Carcinoma in First Line Therapy
Primary epithelial ovarian/ NCT01628380 tubal (FIGO stage IIIC) with complete or partial clinical response after three cycles of neoadjuvant chemotherapy (randomized)
Phase 3 Trial Evaluating Hyperthermic Intraperitoneal Chemotherapy in Upfront Treatment of Stage IIIC Epithelial Ovarian Cancer (CHORINE)
FIGO stage III ovarian cancer after primary/ neoadjuvant chemotherapy (randomized)
Interval debulking Surgery ± Hyperthermic Intraperitoneal Chemotherapy in Stage III Ovarian Cancer
NCT00426257
Platinum-sensitive recurrence NCT01767675 (randomized)
Outcomes After Secondary Cytoreductive Surgery With or Without Carboplatin Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Followed by Systemic Combination Chemotherapy for Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Recurrent ovarian, primary NCT01659554 peritoneal and fallopian tube carcinomas (nonrandomized)
A Phase II Combined Modality Protocol of Debulking Surgery With HIPEC Followed by Intraperitoneal Chemotherapy for the Treatment of Recurrent Ovarian, Primary Peritoneal & Fallopian Tube Cancers
Recurrent ovarian cancer after second-line chemotherapy (randomized)
Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) in Relapse Ovarian Cancer Treatment (CHIPOR)
NCT01376752
FIGO: International Federation of Gynecology and Obstetrics.
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Review – Pölcher, Zivanovic & Chi surgical cytoreduction is increasingly used in the USA and continues to be the subject of ongoing randomized trials with new regimens and new/additional drugs [80]. However, a substantial percentage of the patients (60%) were unable to complete six cycles of cisplatin/paclitaxel ip. chemotherapy, most commonly secondary to abdominal discomfort due to postoperative adhesion barriers and ip. catheter-related complications. Therefore, the European Organization for Research and Treatment of Cancer (Brussels, Belgium) and other international organizations are still unconvinced by available data and still consider this treatment experimental [81]. However, despite only 48% of the patients receiving three or fewer cycles of ip. therapy, the ip. group had significant improvement in median survival compared with the iv. group. An alternative to the postoperative local drug delivery is the intraoperative chemotherapy. For several reasons, there has been increasing interest in the surgical oncology community for combining surgical cytoreduction and hyperthermic ip. drug delivery (HIPEC) in the management of solid tumors whose natural history remains principally localized to the peritoneal cavity. The advantages are as follows: • By giving the chemotherapy intraoperatively, drug exposure is optimal secondary to direct contact with the cancer cells without the barriers of postoperative adhesions;
• Intraoperatively, the chemotherapy can be delivered under highly standardized procedures and the surgeon can guarantee optimal distribution of the chemotherapy, and dwell times can be controlled; • Hyperthermia has been shown to increase the cytotoxic effect of many chemotherapeutic agents by increasing DNA-crosslinking and increasing the tumor penetration [82–84]. A comprehensive review of HIPEC is beyond the scope of this review, but such publications are available [85–92]. This approach has been explored in the treatment of patients with peritoneal malignancies, including pseudomyxoma peritonei, gastric cancer and colorectal malignancies, suggesting a survival benefit using this approach. Unfortunately, there is essentially no evidence from prospective trials to objectively confirm any claimed benefits associated with this approach for patients with advanced EOC. The existing studies on HIPEC are mostly retrospective in nature, heterogeneous with regards to combined inclusion of primary and recurrent disease, and lack robust dose-finding and pharmacok inetic data. Until evidencebased trials yield further data, it is reasonable to conclude that surgical cytoreduction with HIPEC offers a rational, but still investigative, approach in the management of EOC, the use of which should be employed under
Executive summary Background • Ovarian, primary peritoneal and fallopian tube cancers are the most lethal gynecologic malignancies. Prognostic impact of postoperative residual disease • Retrospective studies and meta-analyses have demonstrated and confirmed that the amount of residual disease after cytoreductive surgery (CRS) inversely correlates with progression-free and overall survival. • Increasing optimal cytoreduction rates with more extensive and complex surgical efforts is associated with improved outcomes. Obtaining a higher rate of primary optimal cytoreduction • Advances in surgical training, technique and perioperative care have allowed surgeons to maximize cytoreductive efforts, enabling them to increase the rate of optimal cytoreduction. The role of neoadjuvant chemotherapy • The rate of patients with no gross residual tumor was significantly higher after neoadjuvant chemotherapy when compared with patients who underwent primary CRS. However, the increase in complete gross resection rates after neoadjuvant chemotherapy does not translate into improved outcomes observed in patients who undergo primary CRS. Risks associated with surgical cytoreduction • Surgical cytoreduction is associated with a risk of morbidity and mortality. Single center data quantified the mortality rate after CRS in advanced ovarian cancer to be between 1.4 and 2.5%. • Risk factors for higher mortality in these studies are age, performance status and comorbidities, as well as emergency treatment compared with patients who were treated electively. Video-assisted thoracoscopic surgery • Patients with pleural effusions may benefit from a video-assisted thoracoscopic surgery for diagnosis and intrathoracic cytoreduction. Hyperthermic intraperitoneal drug delivery • Combining surgical cytoreduction and hyperthermic intraperitoneal drug delivery is a rational, but still investigative, approach in the management of epithelial ovarian cancer.
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Cytoreductive surgery for advanced ovarian cancer –
the umbrella of Institutional Review Boardapproved clinical trials. One randomized Phase II trial has been initiated recently at the Memorial Sloan-Kettering Cancer Center [93]. This is a randomized trial designed to compare the efficacy and safety of carboplatin at a dose of 800 mg/m2 administered as HIPEC after secondary CRS for recurrent platinum-sensitive EOC. Patients with minimal residual disease of 5 mm or less will be randomized 1:1 to CRS with HIPEC (arm A; n = 49) or CRS only (arm B; n = 49). Both arms will receive standard postoperative iv. chemotherapy. The primary objective is to determine the proportion of patients who are without evidence of Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J. Clin. 62(1), 10–29 (2012).
2.
Heintz AP, Odicino F, Maisonneuve P et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int. J. Gynecol. Obstet. 95(Suppl. 1), S161–S192 (2006).
3.
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7.
Katsumata N, Yasuda M, Takahashi F et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a Phase 3, open-label, randomised controlled trial. Lancet 374(9698), 1331–1338 (2009). Armstrong DK, Bundy B, Wenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 354(1), 34–43 (2006). These findings prompted the National Cancer Institute (MD, USA) to make a clinical announcement in 2006. Based on the results of these randomized Phase III trials, a combination of intravenous and intraperitoneal administration of chemotherapy conveys a significant survival benefit among women with optimally debulked epithelial ovarian cancer compared with intravenous administration alone. Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365(26), 2473–2483 (2011). Perren TJ, Swart AM, Pfisterer J et al. A Phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365(26), 2484–2496 (2011). Du Bois A, Floquet A, Kim JW et al. Randomized, double-blind, Phase III trial of
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disease progression at 24 months after CRS with or without HIPEC. Current ongoing clinical trials are listed in Table 2 . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international intergroup trial (AGO-OVAR16) J. Clin. Oncol. (Suppl.), Abstract LBA5503 (2013).
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