Objective
Recurrence following primary platinum-based chemotherapy remains a challenge in the treatment of patients with advanced-stage epithelial ovarian cancer. This study examines whether a chemoresponse assay can identify patients who are platinum-resistant prior to treatment.
Study Design
Women (n = 276) with International Federation of Gynecology and Obstetrics stage III-IV ovarian, fallopian, and peritoneal cancer were enrolled in an observational study, and the responsiveness of their tumors was evaluated using a chemoresponse assay. All patients were treated with a platinum/taxane regimen following cytoreductive surgery. Assay responses to carboplatin or paclitaxel were classified as sensitive, intermediate sensitive (IS), or resistant. Association of assay response with progression-free survival (PFS) was analyzed using the Kaplan-Meier method and a Cox regression model.
Results
Patients whose tumors were resistant to carboplatin were at increased risk of disease progression compared to those with nonresistant (sensitive + IS) tumors (median PFS: 11.8 vs 16.6 months, respectively, P < .001), and the association was confirmed after adjusting for other clinical factors (hazard ratio, 1.71; 95% confidence interval, 1.12–2.62; P = .013). Association of assay response to paclitaxel with PFS trended in multivariate analysis (hazard ratio, 1.28; 95% confidence interval, 0.84–1.95; P = .245). For tumors resistant to carboplatin, 59% were sensitive or IS to at least 1 other commonly used agent, demonstrating the ability of the assay to inform treatment decisions beyond the standard platinum/taxane regimen.
Conclusion
Assay resistance to carboplatin is strongly associated with shortened PFS among advanced-stage epithelial ovarian cancer patients treated with carboplatin + paclitaxel therapy, supporting use of this assay to identify patients likely to experience early recurrence on standard platinum-based therapy.
In 2013, it was estimated that there will be 22,240 new cases of ovarian cancer and 14,030 deaths due to this disease in the United States; epithelial ovarian cancer (EOC) represents the leading cause of death from gynecologic malignancies. The poor prognosis observed with EOC is largely attributed to late detection of the disease (ie, once it has already advanced to late stages), as well as intrinsic drug refractory and/or emerging drug resistance to initial chemotherapy. Evidence from randomized clinical trials has established the platinum/taxane combination regimen as standard first-line chemotherapy for patients with advanced-stage EOC, yielding response rates of 60-70%. However, most such patients experience relapse within 1-2 years, and only 30% live >5 years. It is clear that EOC is a heterogeneous disease, and a platinum/taxane combination is not the optimal chemotherapy regimen for all patients.
Efforts have been taken to improve toxicities, response rates, and survival through the use of alternate chemotherapies, the use of different treatment schedules, or the incorporation of biologic agents, with encouraging data recently reported for the latter 2 approaches. Over the last 2 decades, multiple clinical studies have attempted to identify chemotherapy regimens superior to platinum/taxane in the first-line treatment of advanced-stage EOC. Although progression-free survival (PFS) and overall survival (OS) observed in these alternate regimens are no better (and, in many studies, are no worse) than those observed with the platinum/taxane standard, the alternate regimens may be considered to be equivalent in clinical practice.
In EOC, clinically useful markers that identify platinum-resistant tumors, among the overall high number of chemosensitive patients, remain a critical need. If identified early, platinum-resistant EOC patients could benefit from alternate and/or additional therapeutic options in first-line therapy. Moreover, reliable early identification of platinum resistance may allow the development of clinical trials specifically targeting this population with novel alternate therapies.
Chemoresponse assays have been investigated as a method for individualizing chemotherapy treatment decisions and improving outcomes in cancer patients. Recently, a prospective study demonstrated that women with persistent or recurrent EOC who were treated with an assay-sensitive therapy experienced significantly improved PFS and OS compared to those treated with assay-resistant therapies. To further evaluate the clinical relevance of this assay in the primary setting, and in accordance with standards for the reporting of diagnostic accuracy criteria, an observational study was conducted among women with stage III/IV EOC treated by standard-of-care chemotherapy. The primary objective of this study is to determine whether assay response to carboplatin or/and paclitaxel is associated with disease progression among patients with primary EOC following initial treatment with platinum/taxane regimen. Furthermore, this study will evaluate whether this assay can be used to identify patients who are resistant to platinum-based treatment and at high risk of early progression.
Materials and Methods
Study population
Participants were prospectively enrolled in an observational study of women with gynecologic cancers. Tumor samples from 54 institutions were submitted for chemoresponse testing from 2006 through 2010. Women with International Federation of Gynecology and Obstetrics stage III-IV EOC, fallopian tube cancer, and peritoneal cancer treated with carboplatin/paclitaxel-based chemotherapy following initial cytoreductive surgery were included in the study. Patients with a time interval of >2 months between surgery and initiation of chemotherapy, chemotherapy duration >6 months, and/or treatment consisting of >10 cycles of chemotherapy were excluded. The institutional review board at each participating center approved this study, and documented informed consent was obtained from all enrolled patients.
Chemoresponse assay
Details regarding the chemoresponse assay employed in this study (ChemoFx; Precision Therapeutics Inc, Pittsburgh, PA) have been described elsewhere. Briefly, the inhibition of tumor growth was measured at different concentrations of each therapy. The survival fraction of tumor cells at each concentration was calculated as compared to a control (no drug). The summation of survival fraction values over 7 concentrations was computed as the drug response score, which represents the area under the dose-response curve (AUC). A smaller AUC score indicates greater sensitivity to the therapy. Chemoresponse is classified into 1 of 3 categories according to the AUC score: sensitive, intermediate sensitive (IS), or resistant. The classification criterion was defined based on the distribution of AUC scores among an external population of patients with primary EOC. Specifically, the distributions of AUC scores for carboplatin and paclitaxel were established based on referent specimens. Scores ranked at the 25th and 75th percentiles were obtained. A tumor with an AUC score <25th rank was classified as sensitive, between 25th-75th rank as IS, and >75th rank as resistant.
Statistical analysis
The primary endpoint of this study was PFS, calculated from the start of chemotherapy administration until the date of first documented disease recurrence, death, or most recent follow-up. Commonly utilized patient prognostic information was also collected, including: age, Eastern Cooperative Oncology Group performance status, histology, tumor grade, stage, debulking status, and type of chemotherapy administered. The physician(s) at each institution reported all clinical information, which was quality controlled according to a comprehensive monitoring plan. Disease progression was determined by clinical evidence, radiological examination, and/or cancer antigen 125. Optimal debulking was defined as residual tumor of ≤1 cm in maximal dimension at the end of surgery and was reported by enrolling physicians. PFS based on assay response was estimated using the Kaplan-Meier method, and the log rank test was used to compare the differences among sensitive, IS, and resistant patients. Since the primary objective of the current study was to identify platinum-resistant patients, sensitive and IS groups were combined for further analyses. The association of the assay and PFS was also assessed using Cox regression model adjusted for clinical covariates (age, performance status [1-3 vs 0], histology [high-grade serous vs non-high-grade serous], and stage/debulking status [III-suboptimal/IV vs III-optimal]). The hazard ratio (HR) of disease progression for patients treated with resistant vs nonresistant (sensitive + IS) therapy was estimated. Subgroup analyses stratified by age group, performance status, histology/tumor grade, or stage/debulking status were also conducted.
Results
Patients
A total of 462 patients were enrolled in this study, with 276 evaluable for inclusion in the analysis ( Figure 1 ). Patient characteristics are displayed in Table 1 . The median age of the study population was 61 years, and most patients had tumors that were classified as papillary serous (84%), poorly differentiated (83%), stage III (85%), and optimally debulked (72%) ( Table 1 ). The majority (94%) completed 4-8 cycles of chemotherapy. The median follow-up period was 23 months (range, 12–37 months), and 193 (70%) patients experienced disease progression within this time frame. The median PFS was estimated to be 15.9 months (95% confidence interval [CI], 14.3–17.1 months).
| Characteristic | No. patients | % |
|---|---|---|
| Age, y | ||
| Median (range) | 61 (30–85) | |
| <50 | 40 | (14.5) |
| 50–59 | 78 | (28.3) |
| 60–69 | 97 | (35.1) |
| ≥70 | 61 | (22.1) |
| ECOG PS | ||
| 0 | 144 | (52.2) |
| 1 | 63 | (23.8) |
| 2 | 11 | (4.0) |
| 3 | 2 | (0.7) |
| Unknown | 56 | (20.3) |
| Tumor site | ||
| Ovarian | 229 | (83.0) |
| Peritoneal | 32 | (11.6) |
| Fallopian tube | 15 | (5.4) |
| Histology | ||
| Serous | 232 | (84.1) |
| Endometrioid | 8 | (2.9) |
| Clear cell | 6 | (2.2) |
| Mucinous | 3 | (1.1) |
| Others | 27 | (9.8) |
| Tumor grade | ||
| 1 | 12 | (4.4) |
| 2 | 25 | (9.1) |
| 3 | 228 | (82.6) |
| Unknown | 11 | (4.0) |
| Stage | ||
| III | 234 | (84.8) |
| IV | 42 | (15.2) |
| Debulking | ||
| Microscopic | 64 | (23.2) |
| Optimal | 135 | (48.9) |
| Suboptimal | 59 | (21.4) |
| Unknown | 18 | (6.5) |
Chemoresponse assay and clinical outcomes
Assay results for carboplatin were available for 231 patients, with 44 (19.1%) patients identified as resistant to this therapy in the chemoresponse assay. Assay data for paclitaxel were available for 226 patients, 49 (21.7%) of whom were classified as resistant. Assay resistance by age, performance status, histology/grade, and stage/debulking status is summarized in Table 2 . There is no evidence that assay result for either carboplatin or paclitaxel is correlated with patient characteristics. Assay result for carboplatin was significantly associated with clinical outcome ( Figure 2 ). The median PFS was 16.6 and 11.8 months for assay nonresistant (sensitive + IS) and resistant tumors, respectively. Patients displaying assay resistance to carboplatin were at a higher risk of disease progression as compared to those who were nonresistant (HR, 1.87; 95% CI, 1.29–2.70; P < .001). These results were consistent in multivariate analysis after controlling for clinical covariates (HR, 1.71; 95% CI, 1.12–2.62; P = .013) ( Table 3 ). Analysis of subgroups (age group, performance status, histology, stage/debulking status) was also conducted ( Figure 3 ), and the association between PFS and assay result for carboplatin was suggested across all subgroups. The data also suggest that patients with assay resistance to paclitaxel would experience shortened PFS, but the association did not reach the level of statistical significance ( Table 3 ).
| Characteristic | Carboplatin | Paclitaxel | ||||
|---|---|---|---|---|---|---|
| No. patients | No. resistant, n (%) | P value | No. patients | No. resistant, n (%) | P value | |
| Age group, y | .987 | .213 | ||||
| <60 | 100 | 19 (19.0) | 96 | 17 (17.1) | ||
| ≥60 | 131 | 25 (19.1) | 130 | 32 (24.6) | ||
| ECOG PS | .636 | .526 | ||||
| 0 | 126 | 24 (19.1) | 120 | 25 (20.8) | ||
| ≥1 | 59 | 13 (22.0) | 60 | 15 (25.0) | ||
| Tumor grade | .342 | .438 | ||||
| 1-2 | 32 | 8 (25.0) | 30 | 5 (16.7) | ||
| 3 | 190 | 34 (17.9) | 187 | 43 (23.0) | ||
| HGS | .204 | .270 | ||||
| Yes | 165 | 28 (17.0) | 161 | 38 (23.6) | ||
| No | 66 | 16 (24.2) | 65 | 11 (16.9) | ||
| Stage/debulking | .145 | .136 | ||||
| III-Optimal | 143 | 24 (16.8) | 139 | 27 (19.4) | ||
| III-Suboptimal/IV | 76 | 19 (25.0) | 74 | 21 (28.4) | ||
| All | 231 | 44 (19.1) | 226 | 49 (21.7) | ||
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