Objective
We sought to determine the association between tumor responses in vitro to platinum therapy by using the ChemoFx drug response marker and overall survival (OS) after first-line platinum-based chemotherapy in patients with advanced-stage primary ovarian cancer (POC).
Study Design
Chemosensitivity testing was performed in vitro on tumors from 192 POC patients. Tumors were classified as responsive, intermediately responsive, and nonresponsive to chemotherapy. Physicians made all management decisions. Survival status was retrieved from the Social Security Death Index. OS was modeled using Cox proportional hazard regression analysis.
Results
Median OS was 72.5 months for patients with tumors categorized as responsive, 48.6 months for intermediately responsive, and 28.2 months for nonresponsive ( P = .03; hazard ratio, 0.70; 95% confidence interval, 0.50–0.97). The ChemoFx prediction of responses to platinum agents was an independent predictor of OS.
Conclusion
Results of chemosensitivity testing with a drug response marker for therapy was predictive of OS in POC patients.
Platinum-based chemotherapy remains the standard of care for women with advanced epithelial ovarian cancer or fallopian tube or peritoneal carcinoma. While the majority of women will achieve complete clinical remission after cytoreductive surgery and platinum-based chemotherapy, approximately 25–40% of ovarian cancer patients do not have a complete response to front-line, platinum-based treatment. Furthermore, of the patients who do initially respond, the majority will relapse within 14–18 months and ultimately die from disease progression. Therefore, treatment of recurrent ovarian cancer is a significant clinical challenge. A number of chemotherapeutic options exist for recurrent ovarian cancer, including topotecan, gemcitabine, pegylated liposomal doxorubicin, platinum analogs, the taxanes, docetaxel and paclitaxel, and combinations of these agents. The treatment of patients who have early recurrent disease or progress on platinum-based chemotherapy have associated response rates ranging from 5–20%, with limited progression-free survival (PFS) and overall survival (OS).
Since response to chemotherapy cannot be accurately predicted by either clinical or histologic parameters, assessing a tumor’s response to specific chemotherapy treatments in vitro provides the means to predict potential in vivo responses to multiple single-agent or combination therapies before the initiation of any therapy in a patient. The ability to identify patients whose tumors may not respond to standard-of-care, front-line therapy and/or to identify potentially more effective alternate therapy represents an important step toward individualizing treatments for patients. Use of a drug-response marker can provide information on tumor-specific responses before a patient is exposed to therapy, and it may be particularly useful in the setting of ovarian cancer, as multiple, alternate treatments are available that have potential efficacy.
Chemosensitivity testing with ChemoFx (Precision Therapeutics Inc., Pittsburgh, PA) is such a drug-response marker. A previous evaluation of the use of ChemoFx on tumors from >250 primary ovarian cancer (POC) and recurrent ovarian cancer patients reported a direct correlation between ChemoFx prediction of response to the chemotherapy received and the PFS. In this series, the hazard ratio for progression was 2–3 times greater for patients who were treated with a drug or combination of drugs to which their tumor was assessed in vitro as nonresponsive (NR) than for patients who received a drug or drugs to which their tumor was assessed in vitro as responsive (R). Although compelling, OS data had not been reported. Because OS provides a clinically relevant endpoint and is not subject to investigator bias or timing of disease assessments, our primary objective for the current study was to determine the association between OS for patients with stages III/IV POC who were treated with platinum-based therapy and the responsiveness of their tumor specimens to platinum agents, as determined by ChemoFx.
Materials and Methods
Institutional review board approval, where required, was obtained from each of the 11 participating institutions. This clinical study was performed to determine survival outcomes for patients with advanced POC whose physician ordered ChemoFx to be performed on their tumor specimens. Further inclusion criteria for eligible patients included International Federation of Gynecology and Obstetrics (FIGO) stages III-IV disease, with 1 of the following histologic epithelial cell types: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated adenocarcinoma, transitional cell adenocarcinoma, or adenocarcinoma–not otherwise specified; tumor specimen using ChemoFx received from Aug. 1, 1997–Oct. 21, 2003; ChemoFx results for at least 1 platinum drug available; the patient was chemotherapy naive; and the patient was treated with at least 1 cycle of a platinum-based chemotherapy. Final treatment decisions for these women were made by their physicians. In some cases, the physician may have used the results of ChemoFx to assist in the choice of therapy, and it was not known to what extent the results influenced the decision making.
The ChemoFx drug-response marker
Specimens from surgically excised ovarian, fallopian tube, and peritoneal carcinomas were submitted for testing with ChemoFx, as described previously. Primary cultures of cells were grown from the submitted specimens and incubated with a panel of therapeutic drugs selected by the referring physician. Six different drug concentrations were tested for each chemotherapeutic drug, representing the range of concentrations of the drugs in blood levels expected during typical treatment, as well as subtherapeutic and supratherapeutic levels. The percentages of cells surviving after drug treatment were used to construct dose-response curves. Each dose-response curve was reviewed and given a score based on the number of doses that resulted in a reduction of ≥35% in the total surviving cell fraction. The number of doses exceeding the threshold determined the score. For the purposes of this investigation, scores were classified as R, intermediately responsive (IR), or NR.
OS analysis
OS was defined as the time from date of initiation of chemotherapy to date of death. Date of death was determined by an independent epidemiologist consultant, who was blinded to the ChemoFx results. The Social Security Death Index and other standard epidemiologic methods and sources were used to confirm the date of death for each participant; survival status was confirmed by medical chart review as of March 20, 2008, which served as the censoring date for this analysis. OS was calculated from the earliest date of initiation of chemotherapy to date of documented death or censoring date. For analysis, patients were grouped according to whether they received a chemotherapy treatment that was classified R, IR, or NR based on the results of testing their tumor specimen by using ChemoFx. All patients received either carboplatin or cisplatin as a single-agent therapy or in combination with another drug. Since the chemotherapy drugs tested on each tumor and the chemotherapy administered to the patient were chosen by the treating physician, patients may have been treated with combination chemotherapy even though only single agents were tested by ChemoFx in vitro. Each tumor specimen had a ChemoFx result for at least cisplatin and/or carboplatin, so the single-agent platinum score was used for analysis. Specifically, for those patients who received carboplatin as single-agent or combination therapy, the in vitro carboplatin score was used; however, if carboplatin had not been tested in vitro, the cisplatin score was used and vice versa for cisplatin. The Kaplan-Meier method and Cox proportional hazard regression model were used to evaluate the association between ChemoFx results and OS. Statistical analyses were performed using software (SAS, version 9.13; SAS Institute, Cary, NC; and R 2.6; R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 192 women with primary FIGO stages III/IV ovarian cancer met the inclusion criteria. Of these 192 patients, 147 were included in the prior report on PFS. Patients ranged in age from 23–89 years (median, 59.2 years). Additional demographic and clinical data are detailed in Table 1 . All of the eligible women received carboplatin or cisplatin as an element of their treatment ( Table 2 ).
| Characteristics | n |
|---|---|
| Median age, y (range) | 59.2 (23–89) |
| ≤55, n (%) | 68 (35) |
| >55, n (%) | 124 (65) |
| Stage, n (%) | |
| IIIA–IIIB | 17 (9) |
| IIIC–IV | 175 (91) |
| Debulking, n (%) | |
| Optimal | 99 (52) |
| Suboptimal | 93 (48) |
| Treatment | Total no. of patients (n = 192) |
|---|---|
| Carboplatin | 4 |
| Carboplatin/paclitaxel/doxorubicin | 1 |
| Carboplatin/paclitaxel/gemcitabine | 1 |
| Cisplatin | 2 |
| Cisplatin/adriamycin/cyclophosphamide | 1 |
| Cyclophosphamide/carboplatin | 3 |
| Cyclophosphamide/cisplatin | 2 |
| Docetaxel/carboplatin | 3 |
| Etoposide/cisplatin | 1 |
| Gemcitabine/carboplatin | 1 |
| Paclitaxel/carboplatin | 151 |
| Paclitaxel/carboplatin/doxorubicin every other cycle | 1 |
| Paclitaxel/carboplatin/gemcitabine | 7 |
| Paclitaxel/cisplatin | 7 |
| Paclitaxel/cisplatin/cyclophosphamide | 1 |
| Topotecan/carboplatin | 5 |
| Topotecan/cisplatin | 1 |
Heterogeneity of tumor responsiveness
The average number of different drugs or combinations ordered by the physician and tested by using ChemoFx was 8.9 (range, 3–16). Individual patient tumor responses to the different drugs tested are illustrated in Figure 1 . The majority of tumors were tested for and showed response to platinum compounds. Of the 175 tumors that were tested in vitro for carboplatin response, 137 (78%) were categorized as either R or IR, whereas 38 (22%) were NR. Of the 147 tumor specimens tested for cisplatin, only 14 (10%) were NR.
Of the 192 patients, 177 received carboplatin as a single-agent or combination treatment and 15 received cisplatin-based chemotherapy. A carboplatin in vitro response score was available in 163 of the 177 carboplatin-treated patients and thus was used for the survival analysis, while the cisplatin score was used for analysis for the remaining 14 carboplatin-treated patients, as their tumor specimens were not tested for response to carboplatin. Cisplatin scores were available for all 15 patients who received cisplatin as a single-agent or combination therapy and were used for analysis. Using these matching criteria, we identified 35 (90%) of the 39 patients, whose tumors tested NR to the therapy that the patient actually received, but whose tumors had a more R alternate, noncross-resistant drug identified by the assay ( Table 3 ).
