symposium article
Annals of Oncology 24 (Supplement 10): x37–x40, 2013 doi:10.1093/annonc/mdt468
Do we have a new standard in suboptimal debulked disease? M. A. Bookman* & Chair, Ovarian Committee, Gynecologic Oncology Group University of Arizona Cancer Center, Tucson, USA
In the setting of ovarian cancer with high-risk advanced-stage disease, there are a number of treatment options, including neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery (ICS), intraperitoneal (IP) chemotherapy, dose-dense weekly chemotherapy, maintenance chemotherapy, and incorporation of bevacizumab. While individualized decisions arise based on the interpretation of data from randomized, phase III trials, the results are often extrapolated to patient populations not included in the original trial design, based on the clinical judgment, experience, and patient preference. This overview offers a paradigm for initial management of patients with high-risk disease, based on the synthesis of available data and clinical practice. Surgical stage remains the most important prognostic factor [1, 2], and over 80% of newly diagnosed patients will have International Federation of Gynecology and Obstetrics stage IIIC or IV tumors. The second most important prognostic factor is the extent of residual disease after primary cytoreductive surgery (PCS), with the greatest difference in long-term outcomes observed between patients with optimal microscopic disease (no visible residual) compared with optimal macroscopic or suboptimal residual disease [3]. Among patients who undergo initial cytoreductive surgery, ∼80% achieve optimal cytoreduction, including ∼25% within the most favorable (microscopic) subgroup. This leaves ∼20% of patients with suboptimal residual disease. However, with more sophisticated cross-sectional imaging techniques, and the increased acceptance of NACT and ICS, the *Correspondence to: Dr M. A. Bookman, 1515 N Campbell Ave, Tucson, AZ 85724-5024, USA. Tel: +1-520-6263600; Fax: +1-520-6263663; E-mail: [email protected]
population of patients who undergo PCS has become more highly selected, favoring patients with younger age, limited disease, small-volume ascites, and absence of comorbidities. As a result, older-aged patients with more extensive disease, highvolume ascites, and medical comorbidities are more likely to receive NACT. In addition, there has been a trend at some centers for patients to undergo more aggressive primary surgery, with an emphasis on upper abdominal procedures, including resection of multiple hepatic, diaphragmatic, splenic, and gastrointestinal metastases. Taken together, these evolving clinical practices will tend to increase the rate of optimal cytoreduction achieved among those patients selected for primary surgery, leaving fewer patients with surgically documented suboptimal disease. These surgical decisions are largely based on the clinical judgment, as we do not have widely accepted criteria, based on the preoperative imaging or other factors, to define resectability, particularly with the adoption of more aggressive primary surgical techniques. Therefore, the present discussion of treatment options will focus on patients with extensive disease managed with NACT +/− ICS, as well as those with suboptimal residual disease following PCS.
optimal individualized therapy Standards evolve as data from ongoing trials mature. The following considerations will be discussed from the perspective of existing data, clinical consensus, and practical experience.
goals of treatment Patients who undergo NACT, and those with suboptimal residual disease following PCS, represent a population with extremely high-risk for recurrence, regardless of the outcomes
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Treatment options for patients with high-risk advanced-stage ovarian cancer continue to evolve, including consideration of neoadjuvant chemotherapy (NACT), timing of cytoreductive surgery, utilization of intraperitoneal (IP) chemotherapy, adoption of dose-dense weekly paclitaxel (Taxol), addition of maintenance chemotherapy, and incorporation of bevacizumab. Overall, the proportion of patients with suboptimal residual disease has declined, partly as a result of more aggressive primary surgery, and partly through selection of patients for delayed surgery following NACT. However, the risk of recurrence in this population remains high, and treatment decisions need to be individualized, with consideration of clinical goals, avoidance of treatment-related toxicity, control of disease-related symptoms, and minimization of any negative impact on the quality of life. Innovative trials are needed to evaluate early predictors of primary platinum resistance and facilitate the development of non-platinum alternative treatment regimens. Key words: cytoreductive surgery, neoadjuvant chemotherapy, ovarian cancer
symposium article of primary chemotherapy. As such, the goals of treatment are largely palliative, to improve disease-associated symptoms, delay recurrence, and maximize quality of life. From that perspective, it is important to minimize the risks associated with primary therapy, as there is no realistic chance of cure with currently available treatment options.
Annals of Oncology
[11] and platinum-resistant [12] recurrent disease have documented improved PFS with the incorporation of concurrent and maintenance bevacizumab. Taken together, in a patient population with suboptimal residual disease, it would be reasonable to plan primary therapy without bevacizumab, reserving bevacizumab for the setting of recurrent disease, when the benefit–risk ratio is maximized.
selection of patients for NACT
utilization of intravenous (IV) or IP chemotherapy Prior randomized studies have reported improved outcomes with IP chemotherapy in patients with optimal residual disease [6]. While IP therapy is feasible in patients with suboptimal residual disease [7], data are awaited from ongoing randomized trials (GOG0252 and JGOG) to determine whether IP therapy has any advantage in this setting, as well the potential substitution of IP carboplatin for IP cisplatin. At this point, IV chemotherapy is more commonly used in patients with suboptimal disease, but patients might also be considered for IP therapy after completion of NACT-ICS with small-volume residual disease, which is similar to the approach currently utilized in the ongoing NCIC-CTG OV21 trial.
incorporation of bevacizumab Results from ICON7 and GOG0218 suggest that incorporation of bevacizumab will improve PFS, particularly in patients with bulky high-risk disease [8, 9]. A subpopulation analysis of ICON7 also suggested an improvement in median survival within a pre-defined high-risk population [10]. However, an advantage in OS was not initially observed in GOG0218, even though the majority of patients were enrolled with high-risk disease. The most likely explanation for this apparent discordance between the two trials is crossover to commercial bevacizumab post-progression, which was estimated at 30% in GOG0218, compared with essentially no crossover in ICON7. The optimal timing of bevacizumab administration is unknown, including concurrent treatment with primary chemotherapy, extended monotherapy (maintenance), or concurrent treatment in the setting of recurrent disease, and arguments can be made to support each of these options. However, while bevacizumab was generally well tolerated, all agents contribute to toxicity in this high-risk population, and there was clearly increased toxicity associated with concurrent chemotherapy and bevacizumab, compared with extended monotherapy. Randomized, phase III trials in the setting of platinum-sensitive
x | Bookman
choice of chemotherapy regimen All patients should begin with a combination of carboplatin and paclitaxel (Taxol), as there is no regimen with demonstrated superiority [13, 14]. Within commonly established dose ranges, the absolute dose level is not critical, and it can be individualized depending on the vital organ function and tolerance. While it might be argued that single-agent carboplatin is safer and better-tolerated, that is an oversimplification, as the platelet-sparing effect of paclitaxel can facilitate cumulative dosing with carboplatin. Dose-dense weekly paclitaxel has emerged as a strong consideration, based on the JGOG3016 trial [15], and studies in recurrent breast and ovarian cancers also favor a weekly schedule of drug administration, on the basis of toxicity and efficacy. However, the use of 80 mg/m2/week (as in JGOG3016) is associated with frequent dose reductions and delays, due to hematologic toxicity, and there is also a risk of cumulative neurotoxicity, with ∼40% of patients receiving less than six cycles of chemotherapy. Existing data do not support a dose–response relationship with either platinum agents or taxanes, within clinically relevant dose ranges, and the scheduling of paclitaxel appears to have a greater impact than the dose. Therefore, a dose of 60 mg/m2/week might be preferred in this high-risk population, but this has not been validated in a phase III trial. Of interest, the MITO7 trial used fractionated (weekly) carboplatin dosing, at targeted area under the curve (AUC) for concentration and time of 2 mg/ml/ min per week [16]. Initial analysis of PFS showed no statistically significant difference between weekly and three-weekly treatment, but favored weekly treatment based on the tolerability and reduced toxicity. Additional data are awaited from GOG0262, which utilized dose-dense paclitaxel together with conventional three-weekly carboplatin, similar to the JGOG3016 study. At the present time, it is reasonable to use weekly paclitaxel (60–80 mg/m2/ week) with standard three-weekly carboplatin, to maximize efficacy and minimize toxicity.
maintenance chemotherapy Following completion of primary chemotherapy, maintenance has been considered as a non-curative strategy to extend the duration of remission in a chemo-responsive population, although there is clearly an increased risk of cumulative toxicity. In the setting of advanced-stage ovarian cancer, all studies using chemotherapy have been negative [17, 18], with the exception of one study evaluating extended paclitaxel administered on a 3-week schedule [19]. After an early improvement in PFS, evident during a scheduled interim analysis, the study was closed to further accrual by recommendation of the data monitoring committee, compromising long-term clinical outcomes. The Gynecologic Oncology Group (GOG) is
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Two large, randomized trials have compared NACT-ICS with PCS in patients with advanced stage III and IV disease, achieving similar outcomes [4, 5]. Due to advanced disease status among enrolled patients, the median progression-free survival (PFS) and overall survival (OS) were poor, but with similar long-term outcomes on both treatment arms. Advantages associated with NACT include a reduction in perioperative morbidity related to venous thromboembolism, infection, transfusions, and wound healing, which are appealing in this population. Therefore, it is important to consider NACT for patients with advanced-stage disease, including bulky tumor deposits, large-volume ascites, advanced physiologic age, and other comorbidities.
Annals of Oncology
currently completing a phase III maintenance trial (GOG0212) comparing observation with paclitaxel. Pending the results of that study, there is not currently any established role for maintenance chemotherapy in women with advanced-stage ovarian cancer.
symposium article Development of new regimens remains a high priority for clinical trials, and this would be facilitated by collection of serial tumor specimens to define molecular patterns of treatment resistance, and utilization of functional imaging (CT, MRI, or PET) to provide an early biomarker of tumor progression, to permit rapid transition to alternative chemotherapy regimens.
adjustment for physiologic age and comorbidities
alternatives to standard platinum-based chemotherapy This is an important consideration for patients with high-risk disease, as ∼20% will demonstrate disease progression during primary chemotherapy. There are alternative regimens that have similar front-line efficacy, such as carboplatin in combination with either docetaxel (Taxotere) or pegylatedliposomal doxorubicin (PLD), but these would not be appropriate in the setting of primary platinum resistance. Depending on prior therapy, vital organ function, and performance status, individual patients could be managed with single agents, such as PLD, gemcitabine, weekly paclitaxel, or bevacizumab.
conclusion With advances in the selection of patients for cytoreductive surgery, together with more aggressive surgical effort, the proportion of patients with suboptimal residual disease will decline. In addition, more patients with high-risk disease are being considered for NACT, reducing the number of patients referred for PCS. Standard therapy for this population with advanced disease is largely based on the clinical judgment, extrapolated from existing phase III data. At present, the best option appears to be NACT with or without ICS, utilizing weekly paclitaxel and three-weekly carboplatin, with individualized doses based on the age, performance status, and comorbidities, without maintenance chemotherapy, and reserving bevacizumab for management of recurrent disease (Figure 1). Priorities for future studies include the development of alternative treatment regimens and functional biomarkers that predict for resistance to platinum-based chemotherapy.
disclosure The author has declared no conflicts of interest.
Figure 1. Management of suspected high-risk advanced-stage disease. Includes suboptimal residual disease after primary cytoreductive surgery (PCS), or election of neoadjuvant chemotherapy with interval cytoreductive surgery. EOC, epithelial ovarian cancer; AUC, area under the concentration and time curve; PFI, platinum-free interval.
Volume 24 | Supplement 10 | December 2013
doi:10.1093/annonc/mdt468 | x
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Most clinical trials of primary therapy have not enrolled a high proportion of older patients (above age 75), or patients with poor performance status and comorbidities. However, the GOG and other groups have been exploring feasibility and optimized dosing for older patients with and without comorbidities. Until guidelines from ongoing trials are available, it is reasonable to use conservative dosing, such as carboplatin with an AUC 5 mg/ml/min (as adjusted for renal function) and paclitaxel 135 mg/m2every 3 weeks, or paclitaxel 60 mg/m2/week.
symposium article
Annals of Oncology
references
x | Bookman
12.
13.
14.
15.
16.
17.
18.
19.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
1. Winter WE, III, Maxwell GL, Tian C et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007; 25: 3621–3627. 2. Winter WE, III, Maxwell GL, Tian C et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2008; 26: 83–89. 3. du Bois A, Reuss A, Pujade-Lauraine E et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the ArbeitsgemeinschaftGynaekologischeOnkologieStudiengruppeOvarialkarzinom (AGO-OVAR) and the Grouped’InvestigateursNationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 2009; 115: 1234–1244. 4. Vergote I, Tropé CG, Amant F et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943–953. 5. Kehoe S, Hook J, Nankivell M et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. J Clin Oncol 2013; 31: (suppl; abstr 5500). 6. Armstrong DK, Bundy B, Wenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34–43. 7. Morgan MA, Sill MW, Fujiwara K et al. A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2011; 121: 264–268. 8. Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–2483. 9. Perren TJ, Swart AM, Pfisterer J et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–2496. 10. Kristensen G, Perren T, Qian W et al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. J Clin Oncol 2011; 29: (suppl; abstr LBA5006). 11. Aghajanian C, Blank SV, Goff BA et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in
patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30(17): 2039–2045. Pujade-Lauraine E, Hilpert F, Weber B et al. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol 2012; 30: (suppl; abstr LBA5002). Ozols RF, Bundy BN, Greer BE et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage iii ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2003; 21: 3194–3200. Bookman MA, Brady MF, McGuire W et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer InterGroup (GCIG). J Clin Oncol 2009; 27: 1419–1425. Katsumata N, Yasuda M, Takahashi F et al. Japanese Gynecologic Oncology Group. 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 2009; 374: 1331–1338. Pignata S, Scambia G, Lauria R et al. A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicenter Italian Trials in Ovarian Cancer (MITO-7)—European Network of Gynaecological Oncological Trial Groups (ENGOT-ov-10) and Gynecologic Cancer Intergroup (GCIG) trial. J Clin Oncol 2013; 31: (suppl; abstr LBA5501). Pfisterer J, Weber B, Reuss A et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98: 1036–1045. Pecorelli S, Favalli G, Gadducci A et al. Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the after-6 protocol 1. J Clin Oncol 2009; 27: 4642–4648. Markman M, Liu PY, Wilczynski S et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003; 21: 2460–2465.
Annals of Oncology 24 (Supplement 10): x37–x40, 2013 doi:10.1093/annonc/mdt468
Do we have a new standard in suboptimal debulked disease? M. A. Bookman* & Chair, Ovarian Committee, Gynecologic Oncology Group University of Arizona Cancer Center, Tucson, USA
In the setting of ovarian cancer with high-risk advanced-stage disease, there are a number of treatment options, including neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery (ICS), intraperitoneal (IP) chemotherapy, dose-dense weekly chemotherapy, maintenance chemotherapy, and incorporation of bevacizumab. While individualized decisions arise based on the interpretation of data from randomized, phase III trials, the results are often extrapolated to patient populations not included in the original trial design, based on the clinical judgment, experience, and patient preference. This overview offers a paradigm for initial management of patients with high-risk disease, based on the synthesis of available data and clinical practice. Surgical stage remains the most important prognostic factor [1, 2], and over 80% of newly diagnosed patients will have International Federation of Gynecology and Obstetrics stage IIIC or IV tumors. The second most important prognostic factor is the extent of residual disease after primary cytoreductive surgery (PCS), with the greatest difference in long-term outcomes observed between patients with optimal microscopic disease (no visible residual) compared with optimal macroscopic or suboptimal residual disease [3]. Among patients who undergo initial cytoreductive surgery, ∼80% achieve optimal cytoreduction, including ∼25% within the most favorable (microscopic) subgroup. This leaves ∼20% of patients with suboptimal residual disease. However, with more sophisticated cross-sectional imaging techniques, and the increased acceptance of NACT and ICS, the *Correspondence to: Dr M. A. Bookman, 1515 N Campbell Ave, Tucson, AZ 85724-5024, USA. Tel: +1-520-6263600; Fax: +1-520-6263663; E-mail: [email protected]
population of patients who undergo PCS has become more highly selected, favoring patients with younger age, limited disease, small-volume ascites, and absence of comorbidities. As a result, older-aged patients with more extensive disease, highvolume ascites, and medical comorbidities are more likely to receive NACT. In addition, there has been a trend at some centers for patients to undergo more aggressive primary surgery, with an emphasis on upper abdominal procedures, including resection of multiple hepatic, diaphragmatic, splenic, and gastrointestinal metastases. Taken together, these evolving clinical practices will tend to increase the rate of optimal cytoreduction achieved among those patients selected for primary surgery, leaving fewer patients with surgically documented suboptimal disease. These surgical decisions are largely based on the clinical judgment, as we do not have widely accepted criteria, based on the preoperative imaging or other factors, to define resectability, particularly with the adoption of more aggressive primary surgical techniques. Therefore, the present discussion of treatment options will focus on patients with extensive disease managed with NACT +/− ICS, as well as those with suboptimal residual disease following PCS.
optimal individualized therapy Standards evolve as data from ongoing trials mature. The following considerations will be discussed from the perspective of existing data, clinical consensus, and practical experience.
goals of treatment Patients who undergo NACT, and those with suboptimal residual disease following PCS, represent a population with extremely high-risk for recurrence, regardless of the outcomes
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Treatment options for patients with high-risk advanced-stage ovarian cancer continue to evolve, including consideration of neoadjuvant chemotherapy (NACT), timing of cytoreductive surgery, utilization of intraperitoneal (IP) chemotherapy, adoption of dose-dense weekly paclitaxel (Taxol), addition of maintenance chemotherapy, and incorporation of bevacizumab. Overall, the proportion of patients with suboptimal residual disease has declined, partly as a result of more aggressive primary surgery, and partly through selection of patients for delayed surgery following NACT. However, the risk of recurrence in this population remains high, and treatment decisions need to be individualized, with consideration of clinical goals, avoidance of treatment-related toxicity, control of disease-related symptoms, and minimization of any negative impact on the quality of life. Innovative trials are needed to evaluate early predictors of primary platinum resistance and facilitate the development of non-platinum alternative treatment regimens. Key words: cytoreductive surgery, neoadjuvant chemotherapy, ovarian cancer
symposium article of primary chemotherapy. As such, the goals of treatment are largely palliative, to improve disease-associated symptoms, delay recurrence, and maximize quality of life. From that perspective, it is important to minimize the risks associated with primary therapy, as there is no realistic chance of cure with currently available treatment options.
Annals of Oncology
[11] and platinum-resistant [12] recurrent disease have documented improved PFS with the incorporation of concurrent and maintenance bevacizumab. Taken together, in a patient population with suboptimal residual disease, it would be reasonable to plan primary therapy without bevacizumab, reserving bevacizumab for the setting of recurrent disease, when the benefit–risk ratio is maximized.
selection of patients for NACT
utilization of intravenous (IV) or IP chemotherapy Prior randomized studies have reported improved outcomes with IP chemotherapy in patients with optimal residual disease [6]. While IP therapy is feasible in patients with suboptimal residual disease [7], data are awaited from ongoing randomized trials (GOG0252 and JGOG) to determine whether IP therapy has any advantage in this setting, as well the potential substitution of IP carboplatin for IP cisplatin. At this point, IV chemotherapy is more commonly used in patients with suboptimal disease, but patients might also be considered for IP therapy after completion of NACT-ICS with small-volume residual disease, which is similar to the approach currently utilized in the ongoing NCIC-CTG OV21 trial.
incorporation of bevacizumab Results from ICON7 and GOG0218 suggest that incorporation of bevacizumab will improve PFS, particularly in patients with bulky high-risk disease [8, 9]. A subpopulation analysis of ICON7 also suggested an improvement in median survival within a pre-defined high-risk population [10]. However, an advantage in OS was not initially observed in GOG0218, even though the majority of patients were enrolled with high-risk disease. The most likely explanation for this apparent discordance between the two trials is crossover to commercial bevacizumab post-progression, which was estimated at 30% in GOG0218, compared with essentially no crossover in ICON7. The optimal timing of bevacizumab administration is unknown, including concurrent treatment with primary chemotherapy, extended monotherapy (maintenance), or concurrent treatment in the setting of recurrent disease, and arguments can be made to support each of these options. However, while bevacizumab was generally well tolerated, all agents contribute to toxicity in this high-risk population, and there was clearly increased toxicity associated with concurrent chemotherapy and bevacizumab, compared with extended monotherapy. Randomized, phase III trials in the setting of platinum-sensitive
x | Bookman
choice of chemotherapy regimen All patients should begin with a combination of carboplatin and paclitaxel (Taxol), as there is no regimen with demonstrated superiority [13, 14]. Within commonly established dose ranges, the absolute dose level is not critical, and it can be individualized depending on the vital organ function and tolerance. While it might be argued that single-agent carboplatin is safer and better-tolerated, that is an oversimplification, as the platelet-sparing effect of paclitaxel can facilitate cumulative dosing with carboplatin. Dose-dense weekly paclitaxel has emerged as a strong consideration, based on the JGOG3016 trial [15], and studies in recurrent breast and ovarian cancers also favor a weekly schedule of drug administration, on the basis of toxicity and efficacy. However, the use of 80 mg/m2/week (as in JGOG3016) is associated with frequent dose reductions and delays, due to hematologic toxicity, and there is also a risk of cumulative neurotoxicity, with ∼40% of patients receiving less than six cycles of chemotherapy. Existing data do not support a dose–response relationship with either platinum agents or taxanes, within clinically relevant dose ranges, and the scheduling of paclitaxel appears to have a greater impact than the dose. Therefore, a dose of 60 mg/m2/week might be preferred in this high-risk population, but this has not been validated in a phase III trial. Of interest, the MITO7 trial used fractionated (weekly) carboplatin dosing, at targeted area under the curve (AUC) for concentration and time of 2 mg/ml/ min per week [16]. Initial analysis of PFS showed no statistically significant difference between weekly and three-weekly treatment, but favored weekly treatment based on the tolerability and reduced toxicity. Additional data are awaited from GOG0262, which utilized dose-dense paclitaxel together with conventional three-weekly carboplatin, similar to the JGOG3016 study. At the present time, it is reasonable to use weekly paclitaxel (60–80 mg/m2/ week) with standard three-weekly carboplatin, to maximize efficacy and minimize toxicity.
maintenance chemotherapy Following completion of primary chemotherapy, maintenance has been considered as a non-curative strategy to extend the duration of remission in a chemo-responsive population, although there is clearly an increased risk of cumulative toxicity. In the setting of advanced-stage ovarian cancer, all studies using chemotherapy have been negative [17, 18], with the exception of one study evaluating extended paclitaxel administered on a 3-week schedule [19]. After an early improvement in PFS, evident during a scheduled interim analysis, the study was closed to further accrual by recommendation of the data monitoring committee, compromising long-term clinical outcomes. The Gynecologic Oncology Group (GOG) is
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Two large, randomized trials have compared NACT-ICS with PCS in patients with advanced stage III and IV disease, achieving similar outcomes [4, 5]. Due to advanced disease status among enrolled patients, the median progression-free survival (PFS) and overall survival (OS) were poor, but with similar long-term outcomes on both treatment arms. Advantages associated with NACT include a reduction in perioperative morbidity related to venous thromboembolism, infection, transfusions, and wound healing, which are appealing in this population. Therefore, it is important to consider NACT for patients with advanced-stage disease, including bulky tumor deposits, large-volume ascites, advanced physiologic age, and other comorbidities.
Annals of Oncology
currently completing a phase III maintenance trial (GOG0212) comparing observation with paclitaxel. Pending the results of that study, there is not currently any established role for maintenance chemotherapy in women with advanced-stage ovarian cancer.
symposium article Development of new regimens remains a high priority for clinical trials, and this would be facilitated by collection of serial tumor specimens to define molecular patterns of treatment resistance, and utilization of functional imaging (CT, MRI, or PET) to provide an early biomarker of tumor progression, to permit rapid transition to alternative chemotherapy regimens.
adjustment for physiologic age and comorbidities
alternatives to standard platinum-based chemotherapy This is an important consideration for patients with high-risk disease, as ∼20% will demonstrate disease progression during primary chemotherapy. There are alternative regimens that have similar front-line efficacy, such as carboplatin in combination with either docetaxel (Taxotere) or pegylatedliposomal doxorubicin (PLD), but these would not be appropriate in the setting of primary platinum resistance. Depending on prior therapy, vital organ function, and performance status, individual patients could be managed with single agents, such as PLD, gemcitabine, weekly paclitaxel, or bevacizumab.
conclusion With advances in the selection of patients for cytoreductive surgery, together with more aggressive surgical effort, the proportion of patients with suboptimal residual disease will decline. In addition, more patients with high-risk disease are being considered for NACT, reducing the number of patients referred for PCS. Standard therapy for this population with advanced disease is largely based on the clinical judgment, extrapolated from existing phase III data. At present, the best option appears to be NACT with or without ICS, utilizing weekly paclitaxel and three-weekly carboplatin, with individualized doses based on the age, performance status, and comorbidities, without maintenance chemotherapy, and reserving bevacizumab for management of recurrent disease (Figure 1). Priorities for future studies include the development of alternative treatment regimens and functional biomarkers that predict for resistance to platinum-based chemotherapy.
disclosure The author has declared no conflicts of interest.
Figure 1. Management of suspected high-risk advanced-stage disease. Includes suboptimal residual disease after primary cytoreductive surgery (PCS), or election of neoadjuvant chemotherapy with interval cytoreductive surgery. EOC, epithelial ovarian cancer; AUC, area under the concentration and time curve; PFI, platinum-free interval.
Volume 24 | Supplement 10 | December 2013
doi:10.1093/annonc/mdt468 | x
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
Most clinical trials of primary therapy have not enrolled a high proportion of older patients (above age 75), or patients with poor performance status and comorbidities. However, the GOG and other groups have been exploring feasibility and optimized dosing for older patients with and without comorbidities. Until guidelines from ongoing trials are available, it is reasonable to use conservative dosing, such as carboplatin with an AUC 5 mg/ml/min (as adjusted for renal function) and paclitaxel 135 mg/m2every 3 weeks, or paclitaxel 60 mg/m2/week.
symposium article
Annals of Oncology
references
x | Bookman
12.
13.
14.
15.
16.
17.
18.
19.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at University of Waterloo on December 12, 2013
1. Winter WE, III, Maxwell GL, Tian C et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2007; 25: 3621–3627. 2. Winter WE, III, Maxwell GL, Tian C et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2008; 26: 83–89. 3. du Bois A, Reuss A, Pujade-Lauraine E et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the ArbeitsgemeinschaftGynaekologischeOnkologieStudiengruppeOvarialkarzinom (AGO-OVAR) and the Grouped’InvestigateursNationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 2009; 115: 1234–1244. 4. Vergote I, Tropé CG, Amant F et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943–953. 5. Kehoe S, Hook J, Nankivell M et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. J Clin Oncol 2013; 31: (suppl; abstr 5500). 6. Armstrong DK, Bundy B, Wenzel L et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34–43. 7. Morgan MA, Sill MW, Fujiwara K et al. A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2011; 121: 264–268. 8. Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–2483. 9. Perren TJ, Swart AM, Pfisterer J et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–2496. 10. Kristensen G, Perren T, Qian W et al. Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. J Clin Oncol 2011; 29: (suppl; abstr LBA5006). 11. Aghajanian C, Blank SV, Goff BA et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in
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