The role of maintenance therapy and novel taxanes in ovarian cancer

Gynecologic Oncology 102 (2006) 218 – 225 www.elsevier.com/locate/ygyno

The role of maintenance therapy and novel taxanes in ovarian cancer Thomas J. Herzog a,*, Robert L. Coleman b, Maurie Markman b, David Cella c, J. Tate Thigpen d a

c

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University, Herbert Irving Cancer Center, 161 Ft Washington Avenue, New York, NY 10032, USA b Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX 77230, USA Center on Outcomes Research and Education (CORE), Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA d Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA Received 2 August 2005 Available online 7 February 2006

Abstract Objectives. Despite several studies reporting various degrees of success, the role of maintenance chemotherapy in ovarian cancer remains controversial. This article reviews the available data and the controversy surrounding maintenance therapy. In addition, the role of novel taxanes, which may offer an improved therapeutic index and reduced toxicity relative to conventional therapies in this setting, is discussed. Methods. The available randomized clinical data on extended or maintenance therapy in ovarian cancer are reviewed. Results. Available data indicate that patients with ovarian cancer undergoing taxane maintenance chemotherapy exhibit a reduced recurrence rate and a longer progression-free survival. Conclusions. While an additional randomized trial is needed to confirm these benefits and establish maintenance therapy as the standard of care, the authors conclude that maintenance therapy is a valuable option that should be discussed with patients until further data are available. The Gynecologic Oncology Group 212 trial is a randomized clinical trial that is designed to answer whether taxane maintenance therapy offers a survival advantage as well as to determine the impact of such a therapeutic regimen on a patient’s quality of life. This trial is also designed to address some of the questions regarding the role of a novel taxane in maintenance therapy in ovarian cancer. D 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Taxanes; Quality of life; Paclitaxel; Docetaxel; Paclitaxel poliglumex; ABI-007; Epothilone B

Introduction Ovarian cancer continues to be a significant source of morbidity and mortality with 22,220 estimated new cases and 16,210 estimated deaths projected for 2005. Survival correlates with the stage of ovarian cancer at diagnosis: 5-year survival for localized cancer is 94% compared to 29% for patients with distant metastases [1]. Optimal treatment for ovarian cancer involves cytoreduction followed by systemic chemotherapy, typically with 6 cycles of a taxane combined with a platinum agent [2]. In two randomized studies of advanced ovarian cancer, paclitaxel/ cisplatin resulted in significantly longer progression-free survival (PFS) and overall survival (OS) than the cyclophosphamide/cisplatin arm [3,4]. Because most responders will * Corresponding author. Fax: +1 212 305 3412. E-mail address: [email protected] (T.J. Herzog). 0090-8258/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.12.001

relapse within 18 months after completing first-line therapy, ovarian cancer is increasingly recognized as a chronic disease characterized by the sequential administration of active agents. While several agents are available for the treatment of relapsed disease, response rates fall with each subsequent relapse due to the development of drug resistance. One potential strategy to better utilize existing treatment options is to extend tumor response through maintenance therapy; this approach ultimately may improve patient outcome [5]. The concept of continuing chemotherapy beyond 4 to 6 cycles of treatment is a controversial strategy in the management of solid tumors [6 – 8]. The rationale for this approach is that nonresistant, slowly dividing tumor cells which were inadequately exposed to cycle-dependent cytotoxic agents during the initial treatment period may be substantially reduced in number or completely eliminated with the continuation of chemotherapy [9]. In addition, certain antineoplastic agents, including paclitaxel, have profound antiangiogenic effects that

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Table 1 Current evidence on the use of extended therapy in ovarian cancer Study

Design

Hakes et al. [12]

Prospective, randomized comparison of 5 vs. 10 cycles of cyclophosphamide, doxorubicin, and cisplatin Prospective, randomized comparison of 6 vs. 12 cycles of cyclophosphamide, adriamycin, and cisplatin Prospective, randomized comparison of 5 vs. 8 cycles of cisplatin or carboplatin

Bertelsen et al. [13] Lambert et al. [14]

No. of patients

Results

Conclusion

78

Similar response rates and survival between treatment arms

Five cycles are preferable to 10 cycles as it is equally effective and less toxic

202

Similar response rates and survival between treatment arms

233

No significant difference in survival or PFS between treatment arms

No correlation between mean cumulative dose and pathological response and survival Insufficient evidence to justify more than 5 cycles of first-line single agent platinum chemotherapy

may be schedule dependent [10,11]. As a result, continuation of chemotherapy delays tumor growth by targeting both the tumor vasculature and remaining cancer cells. While limited randomized trial data failed to show any advantage for additional treatments or consolidation therapy in ovarian cancer [12 – 14], nonrandomized trials indicate that prolonged treatment with paclitaxel may have some benefit [15,16]. A subsequent randomized study comparing 3 vs. 12 months of paclitaxel maintenance therapy in patients with a complete response to primary therapy demonstrated prolonged PFS in the 12-month arm [2]. However, any benefit of maintenance chemotherapy, whether an increased objective response rate or prolonged PFS or OS, must be balanced

against the added toxicity and potential impact on patients’ quality of life (QOL) associated with additional chemotherapy. Novel taxanes currently available or under development may prove beneficial in maintenance therapy due to the potential for reduced toxicity, greater tumor selectivity, and favorable impact on QOL. The use of maintenance therapy in ovarian cancer and the potential role of novel taxanes in this treatment setting are discussed below. Methods The available randomized clinical data on extended or maintenance therapy in ovarian cancer are summarized in Tables 1 and 2.

Table 2 Maintenance or consolidation treatment following complete response to initial treatment Markman et al. [2]

DePlacido et al. [18]

AGO/GINECO (ASCO 2005, #5007)

Cure et al. [23]

Hall et al. [19] Berek et al. [20]

Sorbe [22]

Varia et al. [21]

Randomized trial of 12 vs. 3 months of maintenance paclitaxel after complete response to initial therapy Prospective, randomized comparison of topotecan (4 cycles) vs. observation

277

Significantly improved PFS

273

No significant difference in survival or PFS between treatment arms

Prospective, randomized comparison of paclitaxel and carboplatin followed by observation vs. paclitaxel and carboplatin followed by topotecan (4 cycles) Prospective, randomized comparison of carboplatin and cyclophosphamide vs. high dose carboplatin and cyclophosphamide with stem cell support Prospective, randomized trial of interferon-a vs. observation Prospective, randomized trial of oregovomab vs. observation

1308

No significant difference in survival or PFS between treatment arms

110 (124 planned)

No significant difference in survival or PFS between treatment arms

300

Prospective, randomized comparison of whole abdominal radiotherapy (WART), chemotherapy, and no further treatment Prospective, randomized comparison of intraperitoneal 32P vs. observation

172

No significant difference in PFS between treatment arms No significant difference in OS or PFS between treatment arms No significant difference in OS. A trend towards an improvement in PFS ( P = 0.05)

Interferon-a does not improve survival following chemotherapy Consolidation therapy with oregovomab did not significantly improve PFS or OS WART improves PFS relative to observation and chemotherapy but does not improve survival

No significant difference in OS or PFS between treatment arms

Intraperitoneal 32P does not decrease the risk of relapse or improve survival in patients with stage III ovarian cancer following negative second-look laparotomy

145

202

Maintenance paclitaxel after complete response to initial therapy improves PFS Consolidation with topotecan does not improve PFS for patients with advanced ovarian cancer who respond to initial chemotherapy Consolidation with topotecan does not improve PFS for patients with advanced ovarian cancer who respond to initial chemotherapy High dose chemotherapy offers no significant increase in OS or PFS following complete clinical remission

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Extended cisplatin-based therapy Three randomized phase III studies compared the efficacy of 8, 10, or 12 cycles of platinum-based chemotherapy with that of 5 or 6 cycles [12 – 14]. Patients with advanced disease were randomized at the beginning of treatment to receive either standard or extended therapy. No differences in response rate or survival were demonstrated between the treatment arms, while toxicity was increased in patients receiving extended therapy.

Paclitaxel maintenance therapy The phase III study initiated by the Southwest Oncology Group (SWOG), and later joined by the Gynecologic Oncology Group (GOG), enrolled advanced stage patients with a complete response to initial therapy with a taxane/platinum combination; patients were randomized to receive either 3 or 12 cycles of monthly paclitaxel as a 3-h infusion at an initial dose of 175 mg/m2 [2]. The monthly schedule was designed to minimize the likelihood of significant neurotoxicity. A prespecified interim analysis revealed statistically significant differences between the two arms: 20/110 patients assigned to the 12-cycle regimen had relapsed, compared to 34/112 patients assigned to the 3cycle regimen; PFS was 28 vs. 21 months, respectively (P = 0.0023). A prespecified early termination boundary of P = 0.005 caused the SWOG Data Monitoring Committee to discontinue the trial as one of the primary endpoints (PFS) was achieved. Analysis of OS was precluded by the limited number of events. Mature results have recently been presented [17]; with 203 events (progression) now recorded, a significant 7-month median PFS advantage remains for the 12-cycle arm (21 months vs. 14 months, P = 0.006).

Consolidation therapy following response to initial therapy A number of randomized trials have evaluated the administration of consolidation therapy following response to initial treatment and are detailed in Table 2 [18 – 23].

Results Critical review of the current evidence on the use of extended or maintenance therapy in ovarian cancer raises some important issues related to the limitations of the available studies. Extended cisplatin-based therapy Three randomized phase III studies showed that extending the standard number of cisplatin-based cycles is not associated with improved response rates or prolonged survival. Although these trials do not support the concept of maintenance therapy, several limitations need to be taken into consideration before dismissing the potential clinical role of maintenance therapy. First, the relatively small sample size of each of these three trials makes it difficult to show an impact on survival. Secondly, patients were randomized at treatment initiation rather than after a complete clinical response. Since 20% to 30% of ovarian cancer patients will be resistant to platinum, delivering 5 or 6 additional courses of cisplatin to such patients would likely be ineffective and dilute any potential positive effect in the extended treatment arm. In retrospect, a more appropriate design would have been to randomize patients after demonstrating that their tumors were platinum-sensitive. Finally, platinum agents may not be appropriate to explore the concept of maintenance therapy in ovarian cancer; platinum-induced cytotoxicity is not highly cycle dependent,

and significant cumulative toxicities are noted with both cisplatin (e.g., emesis, neuropathy, nephrotoxicity) and carboplatin (e.g., bone marrow suppression, hypersensitivity reactions). In contrast, the cytotoxicity of paclitaxel is well established to be highly cycle dependent [9]. Extensive clinical experience suggests that paclitaxel can be delivered for extended periods of time (>1 year); toxicities are generally acceptable with neurotoxicity as the most common cumulative side effect [16,24,25]. Paclitaxel maintenance therapy The rationale for the SWOG-GOG maintenance trial was 3fold: (1) reported prolonged survival in patients receiving 6 courses of paclitaxel [16]; (2) identification of a taxane antiangiogenic effect [10,26,27], which suggests that taxanes may be even more effective if given over a prolonged period; and (3) the documented activity of taxanes in the treatment of ovarian carcinoma [28,29]. While this study clearly demonstrated a prolonged PFS for patients receiving maintenance therapy, the merits of the SWOG-GOG maintenance study have been debated extensively, and practicing oncologists have not uniformly adopted the use of maintenance paclitaxel. Critics of the study have alleged seven major problems with the trial. 1) ‘‘The goal of maintenance therapy must be cure or at the very least prolonged survival. . .’’ A major impediment in the trial’s conclusion is that the study used PFS as a primary end point and as the basis for early closure. However, this criticism ignores the fact that PFS improvement was the initial basis for incorporating both the platinum compounds and taxanes into the standard of care for ovarian carcinoma [3,30]. Furthermore, in studies involving taxane/platinum-based combinations, PFS improvement has predicted an even larger absolute difference in OS. For example, GOG protocol 111 [3] reported a median PFS difference of 5 months (18 vs. 13 months), and this translated into a 14-month difference in median OS (38 vs. 24 months). GOG protocol 114 [31] reported a 6-month difference in median PFS (28 vs. 22 months), and this translated into an 11month difference in OS. GOG protocol 172 [32] demonstrated the same phenomenon with a median PFS difference of 6 months translating into an 17-month difference in median OS. Given the available data, there is reason to believe that, had the study proceeded to its accrual goal of 450 patients without significant crossover of 3-cycle patients to 12 cycles, an even larger difference in OS may have resulted. 2) ‘‘We must wait for the survival analysis before drawing any conclusions about the value of maintenance therapy. . .’’ Along the same lines, others have contended that the study suggests that paclitaxel is not a valid maintenance therapy because the study showed no survival difference. These positions misstate the findings in the study. Because of the crossover, there may not be any meaningful survival analysis, which is not the same as no survival difference. As noted in the

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discussion of the first criticism, a significant survival advantage for the 12-cycle regimen is likely but may not be documented because of crossover. The number of patients who crossed over remains to be reported; therefore, if there will be a statistically meaningful and significant survival difference in the final analysis also remains to be determined. 3) ‘‘The trial closed prematurely and is therefore meaningless. . .’’ This is a false criticism. The prospective design of the trial mandated an interim analysis at the halfway point of accrual. The protocol recommended early closure in the face of extreme differences in PFS. This is a standard ‘‘safety mechanism’’ for randomized trials intended to prevent harm from an inferiorperforming arm. To prevent a statistical type I error, i.e., concluding a difference exists between the two arms when in fact there is none, the statistical bar is generally set 10-fold higher (P < 0.005) than conventional inference parameters. One may argue that the dependence of the interim analysis on PFS was a design flaw, but one cannot say that the study did not meet its prospective goals and closed prematurely. The study design dictated the interim analysis and subsequent closure. 4) ‘‘The cost (dollars and toxicity) of the additional treatment overrides any response or survival benefit. . .’’ With regard to financial cost, the 7-month improvement in median PFS is larger than the differences in PFS observed in studies that resulted in the addition of both platinum compounds and taxanes to front-line treatment [3,25]. Therefore, to suggest that the financial cost of maintenance is not warranted on the basis of results is inconsistent with prior conclusions from frontline studies that altered standard of care. With regard to toxicity, the 23% rate of grade 2 –3 toxicity observed with the 12-cycle regimen is consistent with results of front-line treatment in earlier studies and has generally been considered to be acceptable [4,33]. The dropout rate of 6% in the trial does not suggest excessive or intolerable toxicity, and the greater rate on the 12-cycle regimen (9% vs. 3%) is consistent with the 9month longer duration of therapy in that regimen. Thus, the argument that there is too much cost in terms of both toxicity and finances is not supported by study results. 5) ‘‘These results should not be the basis for the use of maintenance therapy outside of a clinical trial because other studies of maintenance therapy have shown no benefit. . .’’ While other randomized trials of maintenance therapy have not demonstrated a clear benefit for any one modality, none of these studies have employed a taxane or any other antiangiogenic agent [12 –14]. If this point was to be taken at face value, then one negative study of any sort in a particular disease entity would dictate that no further studies ever be done since none would influence future therapy. 6) ‘‘Maintenance therapy should not be used because it might decrease the chances of benefit from retreatment at relapse. . .’’

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There is no definitive evidence to support this contention. Proponents of this criticism generally feel that the ‘‘wait and see’’ approach for post-primary chemotherapy management allows for recovery of effects from therapy and, in the presence of recurrence, increases the chance of repopulation with ‘‘sensitive’’ cells. In the scenario of a recurrent patient 3 months from completing a year of maintenance paclitaxel, proponents would argue that this patient does not retain the same likelihood of response to the same or different agents than a patient off therapy for 15 months. The flaw in this reasoning lies in the likelihood that each of these patients makes it to the 15-month time point. While it may be true that a patient who recurs after maintenance may have a different response to subsequent therapy than one without therapy for 15 months, the patient on maintenance therapy possibly averted earlier recurrence because of treatment. The only way to resolve ascertainment bias in this manner is through the randomization process. 7) ‘‘Maintenance therapy should not be routinely used as it showed no Fclinical benefit. . ._’’ This criticism, raised in an editorial accompanying the trial’s publication in the Journal of Clinical Oncology, contended that the study failed to quantify ‘‘clinical benefit’’ because it did not address QOL, against which any alleged improvement should be benchmarked [5]. However, there are multiple examples of studies without a QOL component that have formed the basis for a change in the standard of care. For example, GOG protocol 111, which led to the widespread use of paclitaxel plus cisplatin in the treatment of ovarian carcinoma, did not include a true multidimensional QOL component; it only measured one small aspect, patient-reported neurotoxicity. Carboplatin was substituted for cisplatin in the combination without the benefit of a true study of QOL associated with the use of the two combinations. Furthermore, the neurotoxicity reported by the National Cancer Institute Common Toxicity Criteria showed the same number of cases of grade 3 –4 neurotoxicity (nine in each arm) with the only grade 4 neurotoxicity reported in the cyclophosphamide arm [3]. Why is it suddenly imperative that a positive maintenance study includes a multidimensional QOL component before it can be the basis for the use of maintenance therapy outside of a clinical trial? Discussion Where do we go now? After decades of attempting to show value for maintenance therapy, a phase III trial has shown an unequivocal advantage in terms of a reduced recurrence rate and improved PFS. This advantage comes at the expense of increased neurotoxicity. However, before this approach becomes the standard of care, a confirmatory trial is needed to show an advantage in OS. Treatment-related neurotoxicity needs to be further assessed and ameliorated. While many of the aforementioned criticisms of maintenance therapy have been dismissed, a number of controversies

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remain as demonstrated by the fact that only a minority of clinicians are administering maintenance therapy to a majority of their eligible patients. A number of other clinical trials have attempted to extend overall survival via administration of additional therapy, but all have failed to date [18 – 23] (Table 2). These include randomized trials of other chemotherapeutics such as topotecan and high-dose combinations, radiation such as whole-abdominal radiation and intraperitoneal 32P, and immunotherapy such as interferon-a and anti-CA125 antibody. The critical question in the SWOG-GOG study is whether or not improved OS can be demonstrated in the maintenance arm. The fact that there still has yet to be a trial completed that demonstrates an OS advantage continues to resonate with clinicians. Clearly, the execution of a randomized trial with OS as the primary end point is pivotal in deciding the question as to whether maintenance therapy will be the new standard in the treatment of women with ovarian cancer who have demonstrated an initial complete clinical response. Quality of life considerations in maintenance therapy Over the past two decades, QOL data reported from solid tumor studies, including ovarian cancer, have shown that chemotherapy – even chemotherapy with fairly significant toxicity – is associated with improved symptoms and QOL among those patients who show radiographic regression [34 – 36]. In ovarian cancer, which generally is responsive to chemotherapy, QOL is sometimes dramatically improved with the introduction of chemotherapy [35]. Less is known about the possible prolonged benefits, or costs, associated with long-term use of chemotherapeutic agents as maintenance therapy. Understanding prior experience of the GOG in studying QOL during chemotherapy for advanced ovarian cancer may indicate what to expect with maintenance regimens. QOL was prospectively evaluated in GOG protocol 152, a study of secondary cytoreduction in advanced ovarian cancer [37]. Adding secondary cytoreductive surgery to 6 courses of paclitaxel and cisplatin chemotherapy did not improve or worsen overall QOL over 12 months when compared with

chemotherapy alone. However, patients in the surgery arm reported significantly less neuropathy at 6 months than those receiving chemotherapy only (38% vs. 54%, P = 0.012) [38]. In GOG protocol 172, despite superiority in PFS and OS with intraperitoneal (IP) paclitaxel and IP cisplatin administration, there was a significant reduction in QOL in the IP cohort. The QOL reduction was related to abdominal symptoms and pain, neurotoxicity, and physical and functional well-being. It was unclear whether the decreased QOL was a result of the IP route of administration, administration of more chemotherapy, or both [38]. Nonetheless, it is apparent that drug delivery certainly influences QOL. No QOL data have been published on maintenance therapy in ovarian cancer. Therefore, QOL with maintenance therapy can only be inferred from available toxicity data, which give a glimpse of QOL but are not sufficient to fully understand the impact of maintenance therapy. Likely QOL issues resulting from maintenance therapy include neuropathy, alopecia, myelosuppression, myalgias, and fatigue. In 12 months of maintenance therapy, Markman and colleagues [2] reported neuropathy frequencies similar to those observed with first-line paclitaxel/platinum therapy in ovarian cancer, suggesting neuropathy might negatively impact QOL during maintenance treatment. Understanding the impact of neuropathy is important but impeded by the fact that reported neuropathy numbers (Table 3) are generally conservative [2– 4,15,39 –44]. If patients were queried directly, for example using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group– Neurotoxicity (Fact/GOG-Ntx) questionnaire [45], a likely finding would be that actual neuropathy is much greater than what is reported as drug toxicity. This may be for several reasons, including the reliance upon spontaneous reporting of problems to signal an event, patient tolerance for toxicity as a means to a valued end, and a general willingness on the part of the patient not to complain unless queried directly. Interestingly, greater neurosensory effects and myalgias in the paclitaxel arm of a study comparing paclitaxel/cisplatin with cyclophosphamide/ cisplatin did not adversely affect QOL [46]. Greater under-

Table 3 Neuropathy by grade in ovarian cancer taxane trials Study

Taxane regimen

Ozols et al. [39]

Paclitaxel 135 mg/m2 over 24 h plus cisplatin 75 mg/m2 Paclitaxel 175 mg/m2 over 3 h plus carboplatin AUC 7.5 Paclitaxel 135 – 175 mg/m2 over 3 h Paclitaxel 135 – 175 mg/m2/over 3 h Paclitaxel regimen over 12 months Paclitaxel 135 mg/m2 over 24 h Paclitaxel 175 mg/m2 over 3 h Docetaxel 100 mg/m2 over 1 h Docetaxel 100 mg/m2 over 1 h Paclitaxel 175 mg/m2 over 3 h Docetaxel 100 mg/m2 over 1 h Paclitaxel poliglumex 175 mg/m2 over 10 min ABI-007 300 mg/m2 over 30 min ABI-007 375 mg/m2 over 30 min

Zanotti et al. [15] Markman et al. [2] McGuire et al. [3] Piccart et al. [4] Verschraegen et al. [40] Rose et al. [41] Vasey et al. [42] Sabbatini et al. [43] Ibrahim et al. [44]

AUC, area under concentration curve; N/A, not available.

Mean no. of cycles

8.5 3 (planned) 12 (planned) 6 (planned) 6 4 3 6 (planned) 6 (planned) 3 N/A-Phase 1

Grade 1 – 2 (%)

Grade 3 (%)

Grade 4 (%)

N/A N/A 53 14 18 24 N/A 33 35 70 44 35 67 50

8 7 0 1 5 4 0.3 0 5 8 2 15 17 50

1 0 0 0 0 0 3 0 0 0 0 0 0 0

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standing of the degree of neuropathy and its impact is needed, particularly when considering that a prolonged exposure to taxanes may potentially increase neurotoxicity. Emerging trials with novel taxanes should provide greater insight into QOL issues during maintenance therapy in ovarian cancer. Use of novel taxanes and taxane-like molecules in ovarian cancer There are several novel taxanes and taxane-like molecules in various stages of development (Table 4) which are designed to enhance the therapeutic index of standard paclitaxel by either overcoming drug resistance or enhancing drug delivery to the tumor. Some of these agents have improved solubility, eliminating the need for toxic solubilizing agents that require the patient to receive premedication. In addition, increased tumor localization and reduced exposure of normal tissue may result in less toxicity than that associated with paclitaxel, including alopecia, myelosuppression, and neuropathy. Ease of administration and reduced toxicity may ultimately result in improved QOL relative to conventional therapy. If a greater therapeutic index is confirmed, these novel drugs may prove to be appropriate for maintenance in ovarian cancer. Docetaxel Docetaxel is a semi-synthetic analog of paclitaxel that is now approved for use in breast cancer, nonsmall cell lung cancer, and prostate cancer. Docetaxel has demonstrated significant activity in paclitaxel-resistant ovarian cancer patients [40,41]; overall response (OR) was about 23% with median survival ranging from 10.2 to 12.7 months. The most severe toxicity was grade 4 granulocytopenia, followed by gastrointestinal toxicity. Severe neuropathy was uncommon. In newly diagnosed stage IC –IV ovarian cancer, docetaxel (75 mg/m2 over 1 h)/carboplatin and paclitaxel (175 mg/m2 over 3 h)/carboplatin resulted in similar PFS (about 15 months) and 2year OS (64.2% and 68.9%, respectively). The docetaxel/ carboplatin combination resulted in significantly less overall and less grade 2 or higher neurotoxicity, but at the expense of Table 4 New and novel taxanes and taxane-like compounds under development Name

Tumor type

Phase of development

Docetaxel

Metastatic breast, prostate, and non-small cell lung cancer Ovarian cancer Ovarian cancer and non-small cell lung cancer Colorectal cancer and metastatic breast cancer Metastatic breast cancer

Approved for use Phase 3 Phase 3

Paclitaxel poliglumex

ABI-007

Aza-epothilone B

Metastatic melanoma, head and neck cancer, solid tumors Ovarian cancer, colorectal cancer, gastric cancer, metastatic breast cancer, non-small cell lung cancer

Phase 2 Approved for use Phase 1/2

223

significantly increased myelosuppression [42]. In summary, docetaxel produces more hematologic side effects, less neurotoxicity, and similar efficacy compared to paclitaxel. Paclitaxel poliglumex (PPX) PPX is macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-l-glutamic acid [47]. PPX is stable in systemic circulation and takes advantage of the enhanced permeation and retention (EPR) effect to passively accumulate in tumor tissue where it progressively releases the active agent paclitaxel. In a preclinical model, tumor exposure to paclitaxel was 12-fold greater when delivered as PPX rather than standard paclitaxel [48]. PPX is water-soluble and can be administered as a short 10- to 20-min infusion without routine medication to prevent hypersensitivity reactions commonly associated with solubilizing agents [43]. PPX is active in both platinum-sensitive and platinumresistant patients with recurrent ovarian cancer [43]. In a heavily pretreated patient population (39 patients [39%] had 1 or 2 prior regimens, and 60 patients (61%) between 3 and 12 prior regimens), the OR rate was 10% (10/99, all partial responses) with an additional 32% (32/99) with stable disease (SD). Median time to progression was 2.1 months. Patients with platinumsensitive disease had an OR of 14% (6/42) and SD in 40% (17/ 42). Patients with platinum-resistant disease had an OR of 7% (4/ 57) and SD in 26% (15/57). Single-agent PPX in recurrent ovarian carcinoma was associated with a 9% incidence of grade 4 neutropenia with no febrile neutropenia. Thirty patients (30%) experienced either grade 2 (n = 15) or grade 3 (n = 15) neuropathy. Notably, no grade 2 or higher alopecia was reported. Epothilones Epothilones are a class of nontaxane cytotoxic drugs that target microtubules in a manner similar to taxanes through microtubule bundling, formation of multipolar spindles, and mitotic arrest [49]. One of these, aza-epothilone B (BMS247550), has shown a broad anticancer activity in several tumor types, including ovarian, breast, and gastrointestinal cancers, with similar toxicity profiles to those of standard taxanes [50]. A recent phase I study evaluated BMS-247550 in 25 patients with solid tumors, of which 10 were ovarian cancer [51]. Following premedication, BMS-247550 was administered as a 1-h infusion every 3 weeks. Partial response was seen in 2 of 10 ovarian cancer patients who were also paclitaxel resistant; dose-limiting toxicities included neutropenia and abdominal pain/nausea. Other phases I and II trials reported less neurotoxicity when BMS-247550 was given in fractionated doses instead of a single dose every 3 weeks [49]. A weekly administration schedule of BMS-247550 is currently under evaluation in GOG protocol 126-M, a phase II trial of patients with recurrent ovarian cancer progressing on or within 6 months of paclitaxel and platinumbased primary therapy. BMS-247550 is administered on days 1, 8, and 15 every 28 days at a dose of 20 mg/m2/week.

Phase 2

Nanoparticle albumin-bound (nab) paclitaxel (ABI-007) ABI-007 is a novel paclitaxel formulation prepared by highpressure homogenization of paclitaxel in the presence of

224

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Fig. 1. GOG 212 trial schema. CCR, clinical complete response; GOG, Gynecologic Oncology Group.

human serum albumin, resulting in a nanoparticle colloidal suspension. Like PPX, ABI-007 is water-soluble, thus eliminating the need to use Cremophor EL [44]. ABI-007 is now approved for use in relapsed breast cancer but has not yet been evaluated in ovarian cancer. Future directions To address the need for a confirmatory trial of maintenance taxane therapy in ovarian cancer, the GOG is conducting a phase III trial in patients who achieve a clinical complete response to 6 cycles of paclitaxel plus carboplatin, including patients that received IP treatment (GOG protocol 212; Fig. 1). Patients register within 3 to 8 weeks of achieving a complete clinical response to front-line therapy and are randomized to (1) PPX 135 mg/m2 monthly for 12 cycles; (2) paclitaxel 135 mg/ m2 monthly for 12 cycles; or (3) observation alone. Patients must have previously received 5 or 6 cycles of chemotherapy with no instance of grade 2 or greater neuropathy. The confirmatory trial includes a provision for dose reduction in those patients with grade 2 or greater neurotoxicity. Results from this trial will help elucidate the benefit of both maintenance chemotherapy and the novel taxane, PPX, in ovarian cancer. The trial will serve to confirm or refute the observations in the completed study of paclitaxel maintenance therapy and will also evaluate whether the new taxane offers similar or better results with a more favorable therapeutic index. Conclusions Studies to date suggest that maintenance chemotherapy with paclitaxel may provide clinical benefit to patients who have achieved a complete response to front-line chemotherapy. While improvement in PFS has been observed, a

confirmatory trial with a survival end point is critical to fully understand the potential benefits of maintenance chemotherapy. New approaches, including the role of novel taxanes with potentially less toxicity and improved tumor selectivity, will be important in optimizing benefit while minimizing toxicity in maintenance chemotherapy. Clinical trials such as GOG 212 will hopefully answer many of the outstanding questions that remain while more fully elucidating the clinical impact of maintenance therapy in the treatment of ovarian cancer. References [1] Cancer Facts and Figures. 2005, American Cancer Society. [2] Markman M, 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(13):2460 – 5. [3] McGuire WP, et al. Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 1996;23(5 Suppl. 12):40 – 7. [4] Piccart MJ, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin – cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92(9):699 – 708. [5] Ozols RF. Maintenance therapy in advanced ovarian cancer: progressionfree survival and clinical benefit. J Clin Oncol 2003;21(13):2451 – 3. [6] Einhorn LH, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 1989;7(3):387 – 91. [7] Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998; 352(9132):930 – 42. [8] Coates A, et al. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. N Engl J Med 1987;317(24):1490 – 5. [9] Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1995;332(15):1004 – 14.

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