After two decades since Black and Speer,3,4
the pioneers of CSRA, developed the tetrazolium dye reduction assay in the 1950's, Hamburger and Salmon10
developed the human cancer stem cell assay in the 1970's. Their success aroused investigators' interest in the chemosensitivity test in solid tumors and it lead them to develop a variety of in vitro
CSRAs. The potential benefits of CSRA are, though they are not achieved yet, as follows; a screening tool for new chemotherapeutic agents, optimizing chemotherapy for individual patients, excluding ineffective agents that can reduce unnecessary complications, chemosensitivity profile according to histology and subtype, establishing profile of cross-resistance and sensitivity before treatment or after recurrence, finding genes and proteins related to chemoresistance and chemosensitivity and matching preclinical in vitro
assay and clinical response.
However, CSRA has a few limitations which should be resolved before it is applied clinically. First, is the tissue sample of the tumor able to represent the whole tumor? Second, the result of CSRA does not correlate to survival. Third, the cost of CSRA is so expensive that the cost-effectiveness should be proved.
Cortazar and Johnson11
analyzed twelve reports which compare chemotherapy based on CSRA with those based on physician's experience. They concluded that the response rate of the chemotherapy based on CSRA is at least similar to that of the chemotherapy based on the physician's experience. The American Society of Clinical Oncology (ASCO) Working Group on CSRAs did not recommended the use of CSRAs to select chemotherapeutic agents for individual patients outside the clinical trial setting.12
Therefore, we designed EDRA-guided chemotherapy in this study based on the taxane and platinum agents, which has been proved to be the most effective.
Cloven et al.13
reported that the rates of EDR in taxanes and platinums are as follows; 22% in paclitaxel, 16% in carboplatin and 10% in cisplatin. Eltabbakh et al.14
reported that one out of seventy-five patients with epithelial ovarian cancer showed EDR to both paclitaxel and cisplatin, and that the patient did not respond to primary chemotherapy with paclitaxel and cisplatin. In this study, we also experienced such results in two patients. Holloway et al.7
reported a significantly lower 5-year survival rate in patients with EDR to platinum than the patients with LDR to platinum (19% vs. 68%).Therefore, it is reasonable to avoid such a combination as both agents show EDR. No significant difference in response is expected when we choose docetaxel instead of paclitaxel15
and also when we choose cisplatin instead of carboplatin.16
Therefore, it would be advisable to replace paclitaxel with docetaxel if the patient showed EDR to paclitaxel and not to docetaxel. We can also replace carboplatin with cisplatin if the patient showed EDR to carboplatin and not to cisplatin.
Though the high cost of EDRA is an obstacle to applying EDRA to every patient, it can be overcome if EDRA is proved to be cost-effective. Orr et al.17
reported the cost-effectiveness of cytoreductive surgery and chemotherapy directed by EDRA in the treatment of women with advanced ovarian cancer. They chose either paclitaxel or cyclophosphamide in combination with platinum according to EDRA after cytoreductive surgery. Although there was no difference in survival whether chemotherapy was directed by EDRA or not, $6,000 of cost was saved when directed by EDRA.
In this study, we applied the strategy to patients receiving primary chemotherapy. If we apply this strategy to recurrent cases, there may be two theoretical reasons that in vitro
resistance can be changed. One reason is that chemosensitive clones have been exterminated after primary chemotherapy but chemoresistant clones grows because of the tumor heterogeneity. The other reason is that tumor genes associated with resistance can be activated after primary chemotherapy. If the above are true, secondary cytoreductive surgery or at least open biopsies are necessary to obtain tissue for EDRA. Tewari et al.18
compared the results of EDRA at primary cytoreductive surgery with the results at second cytoreductive surgery after recurrence. There was approximately 10% difference of the EDR profile in synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis) among 119 patients, and there was no significant difference of the EDR profile in metachronous lesions (specimens from the same patient before and after chemotherapy) in 334 patients. The above authors therefore concluded that it is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis. Loizzi et al.19
reported a case-control study of EDRA-guided chemotherapy in recurrent cases. In the platinum-sensitive group, patients with EDRA-guided therapy had an overall response rate of 65%, compared with 35% in patients who were treated empirically (p=0.02). The overall and progression-free median survival rates were 38 and 15 months in the EDRA group compared with 21 and 7 months in the control group, respectively (p=0.005, overall; p=0.0002, progression free). In the platinum-resistant group, there was no improved outcome in the patients who underwent assay-guided therapy. In multivariate analysis, EDRA-guided therapy was an independent predictor for improved survival.
This study also showed that EDRA may be a possible tool to assess whether triplet chemotherapy is beneficial for a patient. The paclitaxel-carboplatin-gemcitabine triplet has failed to show benefits over the paclitaxel-carboplatin doublet.20-22
If a patient shows EDR to gemcitabine or if a patient does not show EDR to both paclitaxel and carboplatin, the patient who receives triplet therapy may not show any survival benefit but additional toxicity. Therefore, a patient may benefit from a triplet therapy when the patient does not show EDR to gemcitabine or show EDR to both paclitaxel and carboplatin. There were only two cases of triplet in this study and this hypothesis should be evaluated in a larger clinical trial.
In conclusion, this trial was the first case-control study of first-line chemotherapy guided by EDRA in patients with epithelial ovarian cancer. It was possible to choose a combination of taxane and platinum which did not show EDR in most cases and to obtain a good response.