Cancer Metastasis Rev DOI 10.1007/s10555-014-9536-y
Primary debulking surgery and neoadjuvant chemotherapy in the treatment of advanced epithelial ovarian carcinoma Shelly M. Seward & Ira Winer
# Springer Science+Business Media New York 2015
Abstract Surgery and chemotherapy are the standard of care for epithelial ovarian cancer, and it is well established that survival outcomes are improved when the surgery results in no or optimal (less than 1 cm) residual disease. However, for patients with bulky disease that may require extensive or radical procedures to accomplish this goal, the use of neoadjuvant chemotherapy followed by interval debulking surgery to simplify the surgery and minimize morbidity has been suggested. Arguably, this is only ideal if this process produces survival outcomes equivalent to those of primary debulking surgery. The purpose of this article is to review the data surrounding this controversial topic. Keywords Ovarian cancer . Primary debulking surgery . Neoadjuvant chemotherapy
Advanced stage ovarian cancer is a heterogenous disease with a complex array of clinical features associated with outcomes. Stage, histology, grade, age, and disease burden have all been considered standard variables that are used to determine prognosis and shape treatment. Recently, technologic advances used to examine morphologic, molecular, and genetic attributes of ovarian cancer have begun to change the paradigm regarding the origins, characterization, prognosis, treatment, and outcomes of ovarian cancer [4]. While awaiting further improvements in early detection and the development of markers to accurately predict treatment outcomes, the mainstay of primary treatment of advanced epithelial ovarian cancer remains surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy followed by interval cytoreductive surgery.
2 Optimal primary debulking surgery 1 Introduction Ovarian cancer is the leading cause of death from gynecologic malignancy. It is estimated that this year 21,980 new cases will be diagnosed in the USA with 14,270 deaths related to disease. In approximately 70 % or more of cases, the diagnosis is made at metastatic, advanced stage III and IV diseases. While recent survival rates are trending toward improvement, 5-year overall survival rates in advanced disease remain at about 30–40 % [1]. Late diagnosis is often due to vague symptomology associated with this disease as well as the lack of effective screening [2, 3]. S. M. Seward (*) : I. Winer Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI, USA e-mail: [email protected] I. Winer e-mail: [email protected]
As early as 1975, Griffiths described the relationship between postsurgical residual tumor diameter and decreased survival [5]. Using data from Gynecologic Oncology Group (GOG) protocols 52 and 97, Hoskins and colleagues evaluated the effect of residual tumor diameter on survival. They demonstrated a significant decrease in survival with increasing residual disease diameter from microscopic to >2 cm; furthermore, there was no difference in survival among patients with residual disease ≥2 cm in size [6, 7]. Multiple studies since have demonstrated similar results [8]. Currently, the GOG defines optimal cytoreduction as residual disease with a maximum residual tumor diameter of ≤1 cm, and suboptimal residual disease as >1 cm. A modern-era meta-analysis examining stage III and IV ovarian carcinomas showed that each 10 % increase in maximal cytoreduction was associated with a 5.5 % increase in median survival, further confirming the benefits of maximal cytoreductive effort [9].
Cancer Metastasis Rev
In a large single institution retrospective review, Chi and associates evaluated five residual disease categories and their corresponding median overall survival. Those with no gross residual disease had a median overall survival of 106 months, gross disease ≤0.5 cm had 66, 0.6–1.0 cm had 48, 1–2 cm had 33, and >2 cm had 34 months. Statistical analysis demonstrated a significant improvement between no gross residual, gross ≤1 cm, and >1 cm (p1 cm were 45, 32, and 26 months for the PDS group and 38, 27, and 25 months for the NAC group . Among a subgroup of patients with initial tumors 10 cm at enrollment. They cite other institutional studies from the USA and Europe with similar outcomes. However, it becomes difficult to accept these rates in comparison to recent GOG trial survival rates. In GOG protocol 111, a poor prognosis cohort of stage III or IV suboptimally debulked patients; the median overall survival was still superior at 38 months [20]. The 29-month survival reported in this trial is half that seen in GOG protocol 172 with a 65.6 month OS for the intraperitoneal cohort [21]. Another criticism is the overall low rate of achieving optimal cytoreduction in the PDS group. Most expert centers in the USA report rates of 70–75 % for cytoreduction to ≤1 cm. It could be this low rate of optimal cytoreduction that led to the diminished overall survival. The authors discussed that the lower rates of cytoreduction may be due to the purposeful selection of a cohort with bulky initial disease. In an effort to address this point, Chi and colleagues retrospectively evaluated a similar patient cohort (with similar enrollment dates, mix of stage III and IV diseases) from their institution [22]. The rate of optimal debulking was higher at 71 %; median overall survival was higher at 50 months, and median progression free survival was also higher at 17 months. Again, improvements in median OS and PFS were seen when comparing no residual disease, ≤ 1 cm disease, and >1 cm (OS 78, 50, 36 and PFS 24, 17, 13 months). Despite the significantly higher rate of optimal cytoreduction, greater than grade three surgical complications were seen in only 9 %. Of note, the patient population of this retrospective study did differ slightly from the EORTC trial, with fewer stage IV patients (13 vs. 23 %) and a lower median preoperative CA-125 level (610 vs. 1130). In conclusion, their recommendation was made that NAC should be reserved for patients without access to welltrained gynecologic or surgical oncologists, those who cannot tolerate the procedure, or are considered not optimally reducible by an experienced team. A comparison of these studies is seen in Table 1. Recently, early data was presented from another randomized control trial comparing PDS to NAC. The Medical Research Council (MRC) Chemotherapy OR Upfront Table 1
Comparison of outcomes from various studies EORTC
Median OS Median PFS Optimal debulking Grade 3 surgical complications
PDS NACT PDS NACT PDS NACT PDS NACT
CHORUS
29 NS 22.8 30 24.5 12 NS 10.3 12 11.7 41.6 % 16 % 80.6 % 40 % 20.6 % 24 % 6.5 % 14 %
MSKCC NS 50 n/a NS 17 n/a 71 % n/a 9% n/a
Surgery (CHORUS) trial was conducted from 2004 to 2010 in the UK and New Zealand [23]. This non-inferiority trial included 552 advanced ovarian cancer patients with stage III or IV disease randomized to PDS or NAC. The selected cohort had a median tumor size of 8 cm, 25 % were stage IV, and 20 % had a WHO performance status of two or three. There was no significant difference in median OS or PFS for the PDS vs. NAC groups (22.8 vs. 24.5 months, NS and 10.3 vs. 11.7 months, NS). The rate of optimal debulking was 16 % for the PDS group and 40 % in the NAC group. Grade three or higher postoperative complications occurred in 24 % of the PDS group compared to 14 % in the NAC group. They concluded again that NAC provides equivalent outcomes with less toxicity in a select subset of ovarian cancer patients. And also again, early criticisms arose concerning the overall low survival and optimal debulking rates. The full manuscript and editorials are eagerly awaited.
5 Other considerations: tumor biology vs. surgical effort In a review of PDS vs. NAC, a common discussion involves the significance of intrinsic tumor biology as the most important factor in predicting outcome despite the degree of surgical cytoreduction. Simply put, less biologically aggressive cancer should have a lower initial tumor burden, be easier to resect to no residual disease, and have lower/slower rates of recurrence compared to more biologically aggressive tumors. An early GOG study, protocol 52, included an aim to address this issue. Patients who initially presented with large-volume extrapelvic disease despite being optimally cytoreduced had worse outcomes when compared to patients who initially had smallvolume disease and were also optimally cytoreduced, calling into question factors other than cytoreductive surgery as being important in predicting survival [6]. More recently, Aletti et al. reported data opposing this argument [24]. In a cohort of stage IIIC ovarian cancer patients, the amount of residual disease was the only independent predictor of survival on multivariate analysis when looking at age, ASA score, grade, histology, ascites, use of radical surgery, and operative time. In fact, the use of radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. Simply, optimal cytoreduction, regardless of the use of radical procedures, appeared to negate the effect of tumor burden. Other groups have also demonstrated this benefit in cohorts with extensive disease [25]. In a Cochrane review, it was concluded that although the size of residual tumor masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, there is limited evidence to support the conclusion that the surgical procedure is directly responsible for the superior outcome associated with less residual disease [13]. While
Cancer Metastasis Rev
someday advances in technology may provide better markers to predict individual tumor behavior or better nonsurgical treatment options to improve survival, until then, optimal surgical cytoreduction remains a key and modifiable component for a large percentage of women with advanced ovarian cancer.
6 Conclusions Current surgical treatment of women with advanced ovarian cancer can be complex, taking into account patient factors, disease status, and the experience and skills of the surgeon and facility. The heterogenous nature of advanced ovarian cancer and limitation of data from mostly retrospective studies further confounds the issue. However, it seems clear that primary surgical resection of tumor to no residual disease or optimal
Primary debulking surgery and neoadjuvant chemotherapy in the treatment of advanced epithelial ovarian carcinoma Shelly M. Seward & Ira Winer
# Springer Science+Business Media New York 2015
Abstract Surgery and chemotherapy are the standard of care for epithelial ovarian cancer, and it is well established that survival outcomes are improved when the surgery results in no or optimal (less than 1 cm) residual disease. However, for patients with bulky disease that may require extensive or radical procedures to accomplish this goal, the use of neoadjuvant chemotherapy followed by interval debulking surgery to simplify the surgery and minimize morbidity has been suggested. Arguably, this is only ideal if this process produces survival outcomes equivalent to those of primary debulking surgery. The purpose of this article is to review the data surrounding this controversial topic. Keywords Ovarian cancer . Primary debulking surgery . Neoadjuvant chemotherapy
Advanced stage ovarian cancer is a heterogenous disease with a complex array of clinical features associated with outcomes. Stage, histology, grade, age, and disease burden have all been considered standard variables that are used to determine prognosis and shape treatment. Recently, technologic advances used to examine morphologic, molecular, and genetic attributes of ovarian cancer have begun to change the paradigm regarding the origins, characterization, prognosis, treatment, and outcomes of ovarian cancer [4]. While awaiting further improvements in early detection and the development of markers to accurately predict treatment outcomes, the mainstay of primary treatment of advanced epithelial ovarian cancer remains surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy followed by interval cytoreductive surgery.
2 Optimal primary debulking surgery 1 Introduction Ovarian cancer is the leading cause of death from gynecologic malignancy. It is estimated that this year 21,980 new cases will be diagnosed in the USA with 14,270 deaths related to disease. In approximately 70 % or more of cases, the diagnosis is made at metastatic, advanced stage III and IV diseases. While recent survival rates are trending toward improvement, 5-year overall survival rates in advanced disease remain at about 30–40 % [1]. Late diagnosis is often due to vague symptomology associated with this disease as well as the lack of effective screening [2, 3]. S. M. Seward (*) : I. Winer Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI, USA e-mail: [email protected] I. Winer e-mail: [email protected]
As early as 1975, Griffiths described the relationship between postsurgical residual tumor diameter and decreased survival [5]. Using data from Gynecologic Oncology Group (GOG) protocols 52 and 97, Hoskins and colleagues evaluated the effect of residual tumor diameter on survival. They demonstrated a significant decrease in survival with increasing residual disease diameter from microscopic to >2 cm; furthermore, there was no difference in survival among patients with residual disease ≥2 cm in size [6, 7]. Multiple studies since have demonstrated similar results [8]. Currently, the GOG defines optimal cytoreduction as residual disease with a maximum residual tumor diameter of ≤1 cm, and suboptimal residual disease as >1 cm. A modern-era meta-analysis examining stage III and IV ovarian carcinomas showed that each 10 % increase in maximal cytoreduction was associated with a 5.5 % increase in median survival, further confirming the benefits of maximal cytoreductive effort [9].
Cancer Metastasis Rev
In a large single institution retrospective review, Chi and associates evaluated five residual disease categories and their corresponding median overall survival. Those with no gross residual disease had a median overall survival of 106 months, gross disease ≤0.5 cm had 66, 0.6–1.0 cm had 48, 1–2 cm had 33, and >2 cm had 34 months. Statistical analysis demonstrated a significant improvement between no gross residual, gross ≤1 cm, and >1 cm (p1 cm were 45, 32, and 26 months for the PDS group and 38, 27, and 25 months for the NAC group . Among a subgroup of patients with initial tumors 10 cm at enrollment. They cite other institutional studies from the USA and Europe with similar outcomes. However, it becomes difficult to accept these rates in comparison to recent GOG trial survival rates. In GOG protocol 111, a poor prognosis cohort of stage III or IV suboptimally debulked patients; the median overall survival was still superior at 38 months [20]. The 29-month survival reported in this trial is half that seen in GOG protocol 172 with a 65.6 month OS for the intraperitoneal cohort [21]. Another criticism is the overall low rate of achieving optimal cytoreduction in the PDS group. Most expert centers in the USA report rates of 70–75 % for cytoreduction to ≤1 cm. It could be this low rate of optimal cytoreduction that led to the diminished overall survival. The authors discussed that the lower rates of cytoreduction may be due to the purposeful selection of a cohort with bulky initial disease. In an effort to address this point, Chi and colleagues retrospectively evaluated a similar patient cohort (with similar enrollment dates, mix of stage III and IV diseases) from their institution [22]. The rate of optimal debulking was higher at 71 %; median overall survival was higher at 50 months, and median progression free survival was also higher at 17 months. Again, improvements in median OS and PFS were seen when comparing no residual disease, ≤ 1 cm disease, and >1 cm (OS 78, 50, 36 and PFS 24, 17, 13 months). Despite the significantly higher rate of optimal cytoreduction, greater than grade three surgical complications were seen in only 9 %. Of note, the patient population of this retrospective study did differ slightly from the EORTC trial, with fewer stage IV patients (13 vs. 23 %) and a lower median preoperative CA-125 level (610 vs. 1130). In conclusion, their recommendation was made that NAC should be reserved for patients without access to welltrained gynecologic or surgical oncologists, those who cannot tolerate the procedure, or are considered not optimally reducible by an experienced team. A comparison of these studies is seen in Table 1. Recently, early data was presented from another randomized control trial comparing PDS to NAC. The Medical Research Council (MRC) Chemotherapy OR Upfront Table 1
Comparison of outcomes from various studies EORTC
Median OS Median PFS Optimal debulking Grade 3 surgical complications
PDS NACT PDS NACT PDS NACT PDS NACT
CHORUS
29 NS 22.8 30 24.5 12 NS 10.3 12 11.7 41.6 % 16 % 80.6 % 40 % 20.6 % 24 % 6.5 % 14 %
MSKCC NS 50 n/a NS 17 n/a 71 % n/a 9% n/a
Surgery (CHORUS) trial was conducted from 2004 to 2010 in the UK and New Zealand [23]. This non-inferiority trial included 552 advanced ovarian cancer patients with stage III or IV disease randomized to PDS or NAC. The selected cohort had a median tumor size of 8 cm, 25 % were stage IV, and 20 % had a WHO performance status of two or three. There was no significant difference in median OS or PFS for the PDS vs. NAC groups (22.8 vs. 24.5 months, NS and 10.3 vs. 11.7 months, NS). The rate of optimal debulking was 16 % for the PDS group and 40 % in the NAC group. Grade three or higher postoperative complications occurred in 24 % of the PDS group compared to 14 % in the NAC group. They concluded again that NAC provides equivalent outcomes with less toxicity in a select subset of ovarian cancer patients. And also again, early criticisms arose concerning the overall low survival and optimal debulking rates. The full manuscript and editorials are eagerly awaited.
5 Other considerations: tumor biology vs. surgical effort In a review of PDS vs. NAC, a common discussion involves the significance of intrinsic tumor biology as the most important factor in predicting outcome despite the degree of surgical cytoreduction. Simply put, less biologically aggressive cancer should have a lower initial tumor burden, be easier to resect to no residual disease, and have lower/slower rates of recurrence compared to more biologically aggressive tumors. An early GOG study, protocol 52, included an aim to address this issue. Patients who initially presented with large-volume extrapelvic disease despite being optimally cytoreduced had worse outcomes when compared to patients who initially had smallvolume disease and were also optimally cytoreduced, calling into question factors other than cytoreductive surgery as being important in predicting survival [6]. More recently, Aletti et al. reported data opposing this argument [24]. In a cohort of stage IIIC ovarian cancer patients, the amount of residual disease was the only independent predictor of survival on multivariate analysis when looking at age, ASA score, grade, histology, ascites, use of radical surgery, and operative time. In fact, the use of radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. Simply, optimal cytoreduction, regardless of the use of radical procedures, appeared to negate the effect of tumor burden. Other groups have also demonstrated this benefit in cohorts with extensive disease [25]. In a Cochrane review, it was concluded that although the size of residual tumor masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, there is limited evidence to support the conclusion that the surgical procedure is directly responsible for the superior outcome associated with less residual disease [13]. While
Cancer Metastasis Rev
someday advances in technology may provide better markers to predict individual tumor behavior or better nonsurgical treatment options to improve survival, until then, optimal surgical cytoreduction remains a key and modifiable component for a large percentage of women with advanced ovarian cancer.
6 Conclusions Current surgical treatment of women with advanced ovarian cancer can be complex, taking into account patient factors, disease status, and the experience and skills of the surgeon and facility. The heterogenous nature of advanced ovarian cancer and limitation of data from mostly retrospective studies further confounds the issue. However, it seems clear that primary surgical resection of tumor to no residual disease or optimal
