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Assessment of the Applicability of Integrative Tumor Response ANTICANCER RESEARCH 39 : 313-318 (2019) doi:10.21873/anticanres.13113 Assessment of the Applicability of Integrative Tumor Response Assays in Advanced Epithelial Ovarian Cancer JU-HYUN KIM 1, YONG SIK YOON 2, JIN CHEON KIM 2 and YONG-MAN KIM 1 1Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; 2Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Abstract. Aim: To prospectively correlate clinical responses chemotherapy (4). However, although patients have a good to second-line chemotherapy for recurrent epithelial ovarian response to the initial treatment, most tend to experience cancer (EOC) with in vitro integrative tumor-response assay relapse and develop resistance to platinum-based (ITRA) results. Patients and Methods: Forty-four patients with chemotherapy (5-7). Since platinum plays an essential role advanced EOC were enrolled from 2015-2017 at the Asan in the standard therapy for EOC, the development of Medical Center, Seoul, Korea. ITRA comprised of two platinum resistance implies a poor prognosis (8). sequential histoculture drug response assays (HDRAs) of the Anticancer therapy for recurrent ovarian cancer (ROC) is tumor tissues. The first stage was HDRA with paclitaxel– chosen based on platinum sensitivity (9). The standard of care carboplatin, paclitaxel, and carboplatin chemotherapy. The for patients with platinum-sensitive ROC is platinum-based second stage was performed with surviving tumor cells from the chemotherapy (10). In patients with platinum-resistant ROC, first stage using topotecan, belotecan, gemcitabine, non-platinum-based agents, such as pegylated liposomal doxorubicin, ifosfamide, vinorelbine, and etoposide. Results: doxorubicin, topotecan, gemcitabine, and etoposide are The median follow-up period was 23.35 (range=4-35.35) preferred, which have similar clinical efficacies (11). There months. Eighteen patients (40.9%) completed the second-line is no clear guideline on which anticancer therapy should be chemotherapy, based on the ITRA results. The objective chosen. response rate was 38.9%. The clinical response rate was 50%; The histoculture drug response assay (HDRA) is a test that two patients (11.1%) had stable disease. The sensitivity of ITRA evaluates chemosensitivity to a given chemotherapy agent in for predicting response was 85.7% (specificity=18.2%; vitro before treatment is initiated, using tumor tissue obtained accuracy=44.44%). Conclusion: ITRAs had acceptable during surgery to determine the appropriate drug of choice applicability and may help choose second-line chemotherapy (12). The advantages of this assay are its short duration and for patients with advanced EOC. drug delivery similar to the physiological condition due to the maintenance of cell-to-cell or cell-to-substrate interaction and Epithelial ovarian cancer (EOC) is one of the most preservation of physiological tumor cell structure during the challenging and lethal gynecological malignancies (1, 2) test (12-14). The accuracy of HDRA was reported to be with a 5-year survival rate below 45% (3). The current between 74-92.1% in cancer of the head and neck, stomach, standard of care for patients with advanced EOC is ovaries, and colon (12-17). However, with the pre-established debulking surgery combined with paclitaxel and carboplatin HDRA method, only chemosensitivity to first-line therapies can be tested. Hence, once chemoresistance develops, it is impossible to search for alternative chemotherapies. Furthermore, if cancer recurs after the initial surgery and This article is freely accessible online. adjuvant chemotherapy, it is then difficult to obtain cancer tissue. To improve upon this issue, at our Center, we Correspondence to: Professor Yong-Man Kim, MD, Ph.D., pertinently applied an in vitro chemosensitive assay based on Department of Obstetrics and Gynecology, University of Ulsan HDRA: the integrative tumor-response assay (ITRA; Patent College of Medicine, Asan Medical Center, 88 Olympic-ro, 43-gil, No. 10-1046883; the Korean Intellectual Property Office, Songpa-gu, Seoul 05505, Republic of Korea. Tel.: +82 230103640, Fax: +82 24767331, e-mail: [email protected] Seoul, Korea), which was developed by Kim and Moon (18). ITRA is a new in vitro tumor chemosensitivity assay, Key Words: Epithelial ovarian cancer, tumor response assay, performed under near-physiological conditions, that tests for chemotherapy, histoculture drug response assay. sensitivity not only to first-line chemotherapy agents, but also 313 ANTICANCER RESEARCH 39 : 313-318 (2019) second-line agents that can be used in cases with and were lost to follow-up. Consequently, 18 patients underwent second- chemoresistance to first-line drugs, using tumor specimens line chemotherapy based on the ITRA results (Figure 1). obtained during the initial surgery. ITRA is theoretically based ITRA procedure. (i) Tissue preparation: Approximately 200 mg of tumor tissue was obtained to confirm EOC on frozen biopsies; on the HDRA procedure, with methods similar to those used tissue was washed three times in 1-2% povidone-iodine (Besetine in previous studies at our center (15, 16). Solution, Hyundai Pharmaceuticals, Cheonan, Republic of Korea) The current study aimed to evaluate the chemosensitivity and saline solution. The tissue was transported to our laboratory in of primary EOC in patients via ITRA using tumor tissue and tissue transport media (Hanks’s balanced salt solution, 2% sodium to examine the real-world clinical outcomes. bicarbonate, 10% fetal bovine serum (FBS), 1% penicillin- streptomycin, and 0.4% gentamycin) at 4˚C. Patients and Methods The above tissue was then washed three times or more in phosphate-buffered saline (PBS), 1% penicillin-streptomycin, and Patients. This study was conducted with approval of the 0.4% gentamycin. A sterile tissue clamp and scalpel were used to dissect away all non-cancerous parts. The remaining tissue was Institutional Review Board of Asan Medical Center (IRB number: 3 2012-0222). Forty-four patients with EOC were prospectively moved to a new Petri dish and cut into 0.5-1.0 mm pieces. enrolled between March 2015 and December 2017. Informed Chemosensitivity was maintained under near physiological consent was obtained from all patients. We included patients for conditions by preserving the three-dimensional structure of the whom we expected to use adjuvant chemotherapy during surgery, tissue rather than separating the cells. those with a histological diagnosis of epithelial carcinoma of the The resected tissue was washed twice in an antibacterial culture ovaries after primary cytoreductive surgery, those with International solution [RPMI 1640 medium (Gibco, Grand Island, NY, USA), 2% Federation of Obstetrics and Gynaecology (FIGO) stage IIIA to IVb sodium bicarbonate, 10% FBS, 1% penicillin-streptomycin, 0.4% cancer postoperatively, those with an Eastern Cooperative Oncology gentamycin, 1% tetracycline, and 10% chloramphenicol (Carl Roth, performance status ≤2, and ≤80 years old. Patients with a history of Karlsruhe, Germany), 1× tetrazolium salt (MTS; Promega, Madison, chemotherapy or radiotherapy preoperatively were excluded. WI, USA)] and cultured in a CO 2 incubator for 2 hours at 37˚C. The surviving tissue was then stained with tetrazolium salt (MTS; Primary cytoreductive surgery. All patients underwent complete staging Promega, Madison, WI, USA), preventing non-specific drug surgery as the initial treatment. The complete staging surgeries included reactivity to dead cells. The stained and selected tissues were moved total abdominal hysterectomy, bilateral salphingo-oophorectomy, total to a Petri dish and cultured under CO 2 for 24 hours at 37˚C. omentectomy, pelvic and para-aortic lymphadenectomy, and Destained tissue samples of equal size were placed in a 96-well tumorectomy of metastatic lesions. In cases with confirmed tumor plate (TPP, Trasadingen, Switzerland) (Figure 2). invasion, resection surgery of tumor-invaded organs, such as colectomy, (ii) ITRA first-line chemotherapy: The first-line chemotherapy splenectomy, or liver segmentectomy, was also performed. agent was instilled in the wells of primary and secondary reaction plates, and PBS, which was used to wash tissue, was instilled in the Chemotherapy selection. All patients received adjuvant control well. The samples were cultured for 72 hours. All chemotherapy with paclitaxel and carboplatin postoperatively. If chemotherapy agents were refrigerated, and drugs to be used were combination therapy was unsuitable because of severe side-effects, prepared in advance according to their combinations. underlying disease, or advanced age, single-agent paclitaxel or (iii) Analysis of first-line chemotherapy well and instillation of a carboplatin therapy was given. After the initial chemotherapy cycle, second-line chemotherapy agent: The culture solution instilled with patients with a platinum-free interval (PFI) of ≥12 months were the first-line chemotherapy agent was discarded, and 100 μl of 3-(4,5- considered to have platinum-sensitive recurrence; those with PFI ≥6 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT; Sigma, months but ≤12 months had partially platinum-sensitive recurrence, St. Louis, MO, USA) was instilled in the primary wells and cultured and those with PFI <6 months had platinum-resistant recurrence in a CO2 incubator for 3-4 hours at 37˚C. The reaction plates in which (19). Paclitaxel or carboplatin was
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