- Email: [email protected]
Extreme drug resistance is common after prior exposure to paclitaxel
Gynecologic Oncology 106 (2007) 538 – 540 www.elsevier.com/locate/ygyno
Extreme drug resistance is common after prior exposure to paclitaxel John P. Geisler ⁎, Georgiann C. Linnemeier, Amanda J. Thomas, Kelly J. Manahan Indiana Women’s Oncology, Division of Gynecologic Oncology, St. Vincent Hospitals-Indianapolis, 8301 Harcourt Road, Suite 201, Indianapolis, Indiana, USA Received 4 December 2006 Available online 11 June 2007
Abstract Objective. The platinum-free interval (PFI) is an important entity in the treatment of women with epithelial ovarian cancer. The purpose of this study was to determine on clinical samples whether a taxane-free interval (TFI), as defined by in vitro extreme drug resistance assay, existed in women previously exposed to platinum and taxane chemotherapy. Methods. Records were examined from 2003 to 2006 to find all patients with epithelial ovarian cancer who had previous exposure to platinum and taxane therapy. Further examination was done to find all patients who underwent secondary cytoreduction and had their tumor submitted for extreme drug resistance assay. Results. Thirty-four women meeting the above criteria were found. The mean PFI was 25 months (median 18). The mean TFI was 27 months (median 20). Over 44% of the patients have been exposed to more than just a course of platinum and a course of a taxane. In patients having a PFI of ≥12 months, 38.8% had extreme drug resistance (EDR) to carboplatin and 41.9% EDR to cisplatin. Conversely, in patients having a TFI of ≥12 months, 89.7% had EDR to paclitaxel and 82.8% EDR to docetaxel. Conclusions. While only a small percentage have EDR to carboplatin and cisplatin after a PFI of ≥12 months, almost 90% of patients with a TFI ≥12 months showed EDR to paclitaxel in vitro. © 2007 Published by Elsevier Inc. Keywords: Taxane-free interval; Platinum-free interval
Introduction The current treatment of choice for women with epithelial ovarian cancer is debulking surgery. Unfortunately despite aggressive surgical management and adjuvant platinum-based chemotherapy most women have recurrence of disease. The platinum-free interval (PFI) is an important entity in the treatment of women with epithelial ovarian cancer [1]. The Gynecologic Oncology Group has defined 6 months since the most recent platinum-based chemotherapy to recurrence as the period comprising platinum resistant disease. If recurrence occurs after 6 months, the disease is considered platinum sensitive. Chi and colleagues recently explored the platinumfree interval (PFI) and its value in determining when to surgically intervene [2]. They found that the longer the PFI, the better the outcome. In contrast, there is less known about whether a taxane-free interval (TFI) exists. ⁎ Corresponding author. Fax: + 317 415 6707. E-mail address: [email protected] (J.P. Geisler). 0090-8258/$ - see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.ygyno.2007.05.002
The purpose of this study was to determine on clinical patient tumor samples whether TFI, as defined by in vitro extreme drug resistance assay, existed in women previously exposed to platinum and taxane chemotherapy. Materials and methods Hospital and office medical records were examined to find patients undergoing cytoreduction for recurrent epithelial ovarian cancer between July 2003 and August 2006. A further criterion was that the patient had to have received at least one course of chemotherapy previously including a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). Only patients with serous, endometrioid, and adenocarcinoma not otherwise specified (NOS)/ undifferentiated were included. The records were then further analyzed to determine whether the recurrent tumor had been sent for extreme drug resistant assay (Oncotech, Irvine, California). All patients meeting these criteria were studied for age, histology, types of chemotherapy, number of previous courses of chemotherapy, time from most recent platinum, and time from most recent taxane. Since this is a drug resistance assay, intermediate drug resistance (IDR) was included with low drug resistance (LDR) and not extreme drug resistance (EDR). Statistics were performed using SPSS 9.0 (SPSS, Chicago, IL). A course of chemotherapy was defined as exposure to chemotherapy agent for a period of
J.P. Geisler et al. / Gynecologic Oncology 106 (2007) 538–540
539
time with cycles making up the course (i.e., a primary course of carboplatin and paclitaxel is made of 6 cycles). Platinum-free interval was defined as the time (months) from the last exposure to a platinum agent. The taxane-free interval was defined as the time (months) from the last exposure to a taxane.
Results Thirty-four women meeting the above criteria were found. All patients had epithelial ovarian cancer with serous histology being the most common. The mean age of the patients was 59 years old (median 60, range 42–80). The mean number of courses of chemotherapy was 3 with median 2 (range 1–8). Over 44% of the patients had been exposed to more than just a course of platinum and a course of a taxane (35.3% exposed to non-platinum, non-taxane drugs). All 34 patients had received at least one cycle of carboplatin and paclitaxel either sequentially or in combination. Five patients had also received cisplatin while three patients had also received docetaxel. The mean PFI was 25 months (median 18). The mean TFI was 27 months (median 20) (Fig. 1). In patients having a PFI of ≥12 months, 38.8% had EDR to carboplatin and 41.9% EDR to cisplatin. Fig. 2 shows percentage of patients in each PFI. Only one patient had a PFI less than 12 months and so was not included in the data. Over one-third (35.5%) of these patients had been exposed previously to drugs other than platinum and taxanes. Conversely, in patients having a TFI of ≥12 months, 89.7% had EDR to paclitaxel and 82.8% EDR to docetaxel. If the patients with previous exposure to only paclitaxel (and not docetaxel) and a TFI of ≥12 months were evaluated, 81.5% of patients had EDR to docetaxel. Discussion Although it is not always a popular description, ovarian cancer has become a disease with a chronic nature. It is still the most deadly of gynecologic cancers; however, many patients will live for years with the disease present. Because the disease remains, many patients will often be exposed to a wide variety of chemotherapeutic drugs. Often, due to the expanding knowledge of the PFI, patients will undergo exposure to
Fig. 1. Lighter color columns depict number of patients per taxane-free interval. Darker color columns depict number of patients per platinum-free interval. Depicted intervals were: 12–18 months, 19–24 months, and ≥25 months.
Fig. 2. Percentage of patients with low drug resistance (by extreme drug resistance assay) to four drugs is shown. Dark column depicts cisplatin, diagonal striped column depicts carboplatin, vertical striped column depicts paclitaxel, and light column depicts docetaxel. Cisplatin and carboplatin both demonstrate much more common low drug resistance than either taxane at the demonstrated drug-free intervals.
platinum agents multiple times during their life. Even though initial allergic reactions to platinum are rare, allergic reactions increase as the number of times receiving platinum increases [3,4]. Many questions remain, however, regarding whether or not a drug-free interval exists for non-platinum chemotherapies. This is especially important to know so that we do not increase patient’s individual toxicities (i.e., neurotoxicity with paclitaxel) if the chance for drug resistance is high [5]. Recent experimental evidence implicates an increase in CYP2C8 as the mechanism for resistance to paclitaxel [6]. Whether or not this is a permanent increase in vivo is unknown. The current study showed that, despite long TFIs, only a small percentage of patients, 10.3%, showed that their tumors were not resistant to paclitaxel. In contrast, in patients exposed to only paclitaxel and not docetaxel previously, 18.5% of patients tumors demonstrated LDR. This is similar to the 22.4% of patients resistant to paclitaxel responding to docetaxel in the study by Rose et al. [7]. Interestingly, patients with PFIs ≥12 months demonstrated LDRs for carboplatin and cisplatin that were very similar. This fact fits with the current clinical paradigm of ovarian cancer treatment. The low level of low drug resistance, or high level of extreme drug resistance, found for paclitaxel in patients previously exposed to carboplatin and paclitaxel, calls into question the repeat use of single-agent paclitaxel in previously exposed patients. The Memorial Sloan Kettering group and ICON4 both have shown that there may be a synergistic response of paclitaxel and carboplatin in patients with a long PFI [8,9]. Confusing the ICON4 data is that not all women received upfront taxane therapy. Ghamande and colleagues have further shown that weekly paclitaxel may work where higher dose every 3 or 4 week paclitaxel fails [10]. Weekly paclitaxel appears to have a more
540
J.P. Geisler et al. / Gynecologic Oncology 106 (2007) 538–540
favorable toxicity profile than paclitaxel given by a longer dosing interval [11]. In vitro drug resistance assays cannot predict whether or not a patient’s tumor is resistant to the proposed mechanism of action of weekly paclitaxel, antiangiogenesis. Drug sensitivity [12] inherently is more attractive than drug resistance tests. Although both assays help individualization of therapy, both assays suffer from their in vitro status. Holloway and colleagues have shown that correlation of the EDR in vitro assay and patient outcome exists [13]. Tewari and colleagues demonstrated in their patient population that EDR assays from primary and secondary surgeries did not differ significantly [14,15]. That exact exposure of previous chemotherapy agents was not available which may explain the differences in their results. The current paper does not try and correlate the in vitro assay results with clinical outcomes, rather this paper has tried to demonstrate that patients with previous taxane exposure demonstrate in vitro drug resistance commonly to at least the same taxane. In vitro data do not preclude the possibility that clinical outcomes may be different than what is predicted. However, these data do show that although a platinum-free interval is supported by in vitro EDR assay data, there is no support for a true taxane-free interval. This is supported by the fact that less than 50% of patients’ tumors will be resistant to platinum after prolonged drug-free interval yet greater than 80% of patients’ tumors will be resistant to taxanes after similar drugfree intervals.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgment Women’s Oncology Research and Development Foundation (wordoncancer.org).
[12]
[13]
References [1] Bookman MA. Extending the platinum-free interval in recurrent ovarian cancer: the role of topotecan in second-line chemotherapy. Oncologist 1999;4:87–94. [2] Chi DS, McCaughty K, Schwabenbauer S, Huh J, Hummer A, Venkatraman E, et al. Guidelines and selection criteria for secondary cytoreductive
[14] [15]
surgery in patients with recurrent epithelial ovarian carcinoma. Soc Gynecol Oncol 2006. Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT, Gershenson DM, Wolf JK. Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with gynecologic malignancies. Gynecol Oncol 2001;82:550–8. Rose PG, Fusco N, Smrekar M, Mossbruger K, Rodriguez M. Successful administration of carboplatin in patients with clinically documented carboplatin hypersensitivity. Gynecol Oncol 2003;89:429–33. Tresukosol D, Kudelka AP, Gonzales de Leon C, Edwards CL, Freedman RS, Mante R, et al. Paclitaxel retreatment in patients with platinum and paclitaxel resistant ovarian cancer. Eur J Gynaecol Oncol 1996;17:188–91. Garcia-Martin E, Pizarro RM, Martinez C, Gutierrez-Martin Y, Perez G, Jover R, et al. Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8. Pharmacogenomics 2006;7:575–85. Rose PG, Blessing JA, Ball HG, Hoffman J, Warshal D, Degeest K, et al. A phase II study of docetaxel in paclitaxel resistant ovarian and peritoneal carcinoma. A Gynecologic Oncology Group study. Soc Gynecol Oncol 2002. Dizon DS, Dupont J, Anderson S, Sabbatini P, Hummer A, Aghajanian C, et al. Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel. The Memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol 2003;91:584–90. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, et al. ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGOOVAR-2.2 trial. Lancet 2003;361:2099–106. Ghamande S, Lele S, Marchetti D, Baker T, Odunsi K. Weekly paclitaxel in patients with recurrent or persistent advanced ovarian cancer. Int J Gynecol Cancer 2003;13:142–7. Fennelly D, Aghajanian C, Shapiro F, O’Flaherty C, McKenzie M, O’Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187–92. Konecny G, Crohns C, Pegram M, Felber M, Lude S, Kurbacher C, et al. Correlation of drug response with the ATP tumor chemosensitivity assay in primary FIGO stage III ovarian cancer. Gynecol Oncol 2000;77:258–63. Holloway RW, Mehta RS, Finkler NJ, Li KT, McLaren CE, Parker RJ, et al. Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 2002; 87:8–16. Tewari K, Manetta A. In vitro chemosensitivity testing and mechanisms of drug resistance. Curr Oncol Rep 1999;1:77–84. Tewari KS, Mehta RS, Burger RA, Yu IR, Kyshtoobayeva AS, Monk BJ, et al. Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma. Gynecol Oncol 2005;98:360–8.
Extreme drug resistance is common after prior exposure to paclitaxel John P. Geisler ⁎, Georgiann C. Linnemeier, Amanda J. Thomas, Kelly J. Manahan Indiana Women’s Oncology, Division of Gynecologic Oncology, St. Vincent Hospitals-Indianapolis, 8301 Harcourt Road, Suite 201, Indianapolis, Indiana, USA Received 4 December 2006 Available online 11 June 2007
Abstract Objective. The platinum-free interval (PFI) is an important entity in the treatment of women with epithelial ovarian cancer. The purpose of this study was to determine on clinical samples whether a taxane-free interval (TFI), as defined by in vitro extreme drug resistance assay, existed in women previously exposed to platinum and taxane chemotherapy. Methods. Records were examined from 2003 to 2006 to find all patients with epithelial ovarian cancer who had previous exposure to platinum and taxane therapy. Further examination was done to find all patients who underwent secondary cytoreduction and had their tumor submitted for extreme drug resistance assay. Results. Thirty-four women meeting the above criteria were found. The mean PFI was 25 months (median 18). The mean TFI was 27 months (median 20). Over 44% of the patients have been exposed to more than just a course of platinum and a course of a taxane. In patients having a PFI of ≥12 months, 38.8% had extreme drug resistance (EDR) to carboplatin and 41.9% EDR to cisplatin. Conversely, in patients having a TFI of ≥12 months, 89.7% had EDR to paclitaxel and 82.8% EDR to docetaxel. Conclusions. While only a small percentage have EDR to carboplatin and cisplatin after a PFI of ≥12 months, almost 90% of patients with a TFI ≥12 months showed EDR to paclitaxel in vitro. © 2007 Published by Elsevier Inc. Keywords: Taxane-free interval; Platinum-free interval
Introduction The current treatment of choice for women with epithelial ovarian cancer is debulking surgery. Unfortunately despite aggressive surgical management and adjuvant platinum-based chemotherapy most women have recurrence of disease. The platinum-free interval (PFI) is an important entity in the treatment of women with epithelial ovarian cancer [1]. The Gynecologic Oncology Group has defined 6 months since the most recent platinum-based chemotherapy to recurrence as the period comprising platinum resistant disease. If recurrence occurs after 6 months, the disease is considered platinum sensitive. Chi and colleagues recently explored the platinumfree interval (PFI) and its value in determining when to surgically intervene [2]. They found that the longer the PFI, the better the outcome. In contrast, there is less known about whether a taxane-free interval (TFI) exists. ⁎ Corresponding author. Fax: + 317 415 6707. E-mail address: [email protected] (J.P. Geisler). 0090-8258/$ - see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.ygyno.2007.05.002
The purpose of this study was to determine on clinical patient tumor samples whether TFI, as defined by in vitro extreme drug resistance assay, existed in women previously exposed to platinum and taxane chemotherapy. Materials and methods Hospital and office medical records were examined to find patients undergoing cytoreduction for recurrent epithelial ovarian cancer between July 2003 and August 2006. A further criterion was that the patient had to have received at least one course of chemotherapy previously including a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). Only patients with serous, endometrioid, and adenocarcinoma not otherwise specified (NOS)/ undifferentiated were included. The records were then further analyzed to determine whether the recurrent tumor had been sent for extreme drug resistant assay (Oncotech, Irvine, California). All patients meeting these criteria were studied for age, histology, types of chemotherapy, number of previous courses of chemotherapy, time from most recent platinum, and time from most recent taxane. Since this is a drug resistance assay, intermediate drug resistance (IDR) was included with low drug resistance (LDR) and not extreme drug resistance (EDR). Statistics were performed using SPSS 9.0 (SPSS, Chicago, IL). A course of chemotherapy was defined as exposure to chemotherapy agent for a period of
J.P. Geisler et al. / Gynecologic Oncology 106 (2007) 538–540
539
time with cycles making up the course (i.e., a primary course of carboplatin and paclitaxel is made of 6 cycles). Platinum-free interval was defined as the time (months) from the last exposure to a platinum agent. The taxane-free interval was defined as the time (months) from the last exposure to a taxane.
Results Thirty-four women meeting the above criteria were found. All patients had epithelial ovarian cancer with serous histology being the most common. The mean age of the patients was 59 years old (median 60, range 42–80). The mean number of courses of chemotherapy was 3 with median 2 (range 1–8). Over 44% of the patients had been exposed to more than just a course of platinum and a course of a taxane (35.3% exposed to non-platinum, non-taxane drugs). All 34 patients had received at least one cycle of carboplatin and paclitaxel either sequentially or in combination. Five patients had also received cisplatin while three patients had also received docetaxel. The mean PFI was 25 months (median 18). The mean TFI was 27 months (median 20) (Fig. 1). In patients having a PFI of ≥12 months, 38.8% had EDR to carboplatin and 41.9% EDR to cisplatin. Fig. 2 shows percentage of patients in each PFI. Only one patient had a PFI less than 12 months and so was not included in the data. Over one-third (35.5%) of these patients had been exposed previously to drugs other than platinum and taxanes. Conversely, in patients having a TFI of ≥12 months, 89.7% had EDR to paclitaxel and 82.8% EDR to docetaxel. If the patients with previous exposure to only paclitaxel (and not docetaxel) and a TFI of ≥12 months were evaluated, 81.5% of patients had EDR to docetaxel. Discussion Although it is not always a popular description, ovarian cancer has become a disease with a chronic nature. It is still the most deadly of gynecologic cancers; however, many patients will live for years with the disease present. Because the disease remains, many patients will often be exposed to a wide variety of chemotherapeutic drugs. Often, due to the expanding knowledge of the PFI, patients will undergo exposure to
Fig. 1. Lighter color columns depict number of patients per taxane-free interval. Darker color columns depict number of patients per platinum-free interval. Depicted intervals were: 12–18 months, 19–24 months, and ≥25 months.
Fig. 2. Percentage of patients with low drug resistance (by extreme drug resistance assay) to four drugs is shown. Dark column depicts cisplatin, diagonal striped column depicts carboplatin, vertical striped column depicts paclitaxel, and light column depicts docetaxel. Cisplatin and carboplatin both demonstrate much more common low drug resistance than either taxane at the demonstrated drug-free intervals.
platinum agents multiple times during their life. Even though initial allergic reactions to platinum are rare, allergic reactions increase as the number of times receiving platinum increases [3,4]. Many questions remain, however, regarding whether or not a drug-free interval exists for non-platinum chemotherapies. This is especially important to know so that we do not increase patient’s individual toxicities (i.e., neurotoxicity with paclitaxel) if the chance for drug resistance is high [5]. Recent experimental evidence implicates an increase in CYP2C8 as the mechanism for resistance to paclitaxel [6]. Whether or not this is a permanent increase in vivo is unknown. The current study showed that, despite long TFIs, only a small percentage of patients, 10.3%, showed that their tumors were not resistant to paclitaxel. In contrast, in patients exposed to only paclitaxel and not docetaxel previously, 18.5% of patients tumors demonstrated LDR. This is similar to the 22.4% of patients resistant to paclitaxel responding to docetaxel in the study by Rose et al. [7]. Interestingly, patients with PFIs ≥12 months demonstrated LDRs for carboplatin and cisplatin that were very similar. This fact fits with the current clinical paradigm of ovarian cancer treatment. The low level of low drug resistance, or high level of extreme drug resistance, found for paclitaxel in patients previously exposed to carboplatin and paclitaxel, calls into question the repeat use of single-agent paclitaxel in previously exposed patients. The Memorial Sloan Kettering group and ICON4 both have shown that there may be a synergistic response of paclitaxel and carboplatin in patients with a long PFI [8,9]. Confusing the ICON4 data is that not all women received upfront taxane therapy. Ghamande and colleagues have further shown that weekly paclitaxel may work where higher dose every 3 or 4 week paclitaxel fails [10]. Weekly paclitaxel appears to have a more
540
J.P. Geisler et al. / Gynecologic Oncology 106 (2007) 538–540
favorable toxicity profile than paclitaxel given by a longer dosing interval [11]. In vitro drug resistance assays cannot predict whether or not a patient’s tumor is resistant to the proposed mechanism of action of weekly paclitaxel, antiangiogenesis. Drug sensitivity [12] inherently is more attractive than drug resistance tests. Although both assays help individualization of therapy, both assays suffer from their in vitro status. Holloway and colleagues have shown that correlation of the EDR in vitro assay and patient outcome exists [13]. Tewari and colleagues demonstrated in their patient population that EDR assays from primary and secondary surgeries did not differ significantly [14,15]. That exact exposure of previous chemotherapy agents was not available which may explain the differences in their results. The current paper does not try and correlate the in vitro assay results with clinical outcomes, rather this paper has tried to demonstrate that patients with previous taxane exposure demonstrate in vitro drug resistance commonly to at least the same taxane. In vitro data do not preclude the possibility that clinical outcomes may be different than what is predicted. However, these data do show that although a platinum-free interval is supported by in vitro EDR assay data, there is no support for a true taxane-free interval. This is supported by the fact that less than 50% of patients’ tumors will be resistant to platinum after prolonged drug-free interval yet greater than 80% of patients’ tumors will be resistant to taxanes after similar drugfree intervals.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Acknowledgment Women’s Oncology Research and Development Foundation (wordoncancer.org).
[12]
[13]
References [1] Bookman MA. Extending the platinum-free interval in recurrent ovarian cancer: the role of topotecan in second-line chemotherapy. Oncologist 1999;4:87–94. [2] Chi DS, McCaughty K, Schwabenbauer S, Huh J, Hummer A, Venkatraman E, et al. Guidelines and selection criteria for secondary cytoreductive
[14] [15]
surgery in patients with recurrent epithelial ovarian carcinoma. Soc Gynecol Oncol 2006. Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT, Gershenson DM, Wolf JK. Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with gynecologic malignancies. Gynecol Oncol 2001;82:550–8. Rose PG, Fusco N, Smrekar M, Mossbruger K, Rodriguez M. Successful administration of carboplatin in patients with clinically documented carboplatin hypersensitivity. Gynecol Oncol 2003;89:429–33. Tresukosol D, Kudelka AP, Gonzales de Leon C, Edwards CL, Freedman RS, Mante R, et al. Paclitaxel retreatment in patients with platinum and paclitaxel resistant ovarian cancer. Eur J Gynaecol Oncol 1996;17:188–91. Garcia-Martin E, Pizarro RM, Martinez C, Gutierrez-Martin Y, Perez G, Jover R, et al. Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8. Pharmacogenomics 2006;7:575–85. Rose PG, Blessing JA, Ball HG, Hoffman J, Warshal D, Degeest K, et al. A phase II study of docetaxel in paclitaxel resistant ovarian and peritoneal carcinoma. A Gynecologic Oncology Group study. Soc Gynecol Oncol 2002. Dizon DS, Dupont J, Anderson S, Sabbatini P, Hummer A, Aghajanian C, et al. Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel. The Memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol 2003;91:584–90. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, et al. ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGOOVAR-2.2 trial. Lancet 2003;361:2099–106. Ghamande S, Lele S, Marchetti D, Baker T, Odunsi K. Weekly paclitaxel in patients with recurrent or persistent advanced ovarian cancer. Int J Gynecol Cancer 2003;13:142–7. Fennelly D, Aghajanian C, Shapiro F, O’Flaherty C, McKenzie M, O’Connor C, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187–92. Konecny G, Crohns C, Pegram M, Felber M, Lude S, Kurbacher C, et al. Correlation of drug response with the ATP tumor chemosensitivity assay in primary FIGO stage III ovarian cancer. Gynecol Oncol 2000;77:258–63. Holloway RW, Mehta RS, Finkler NJ, Li KT, McLaren CE, Parker RJ, et al. Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 2002; 87:8–16. Tewari K, Manetta A. In vitro chemosensitivity testing and mechanisms of drug resistance. Curr Oncol Rep 1999;1:77–84. Tewari KS, Mehta RS, Burger RA, Yu IR, Kyshtoobayeva AS, Monk BJ, et al. Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma. Gynecol Oncol 2005;98:360–8.