340 Clinical report

The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients Tamar Safraa, Noam Asnaa, Anat Veizmana, Shulem Shpigela, Dianna Matcejevskya, Moshe Inbara and Dan Grisarub The aim of this study was to evaluate progression-free survival, overall survival (OS), response rate (RR), and clinical benefit in recurrent ovarian cancer patients treated with gemcitabine and carboplatin and to compare the outcome among platinum-resistant and platinum-sensitive patients. A retrospective study using the medical records of patients diagnosed and treated for recurrent epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma with gemcitabine and carboplatin from 2005 through 2012 at the Tel Aviv Sourasky Medical Center. The treatment regimen was carboplatin (area under the curve = 5) administered on day 1 and gemcitabine 850 mg/m2 administered on days 1 and 8 in a 21-day cycle. Seventy patients with a median age of 57 years (range: 38–86) were included in the study. Most patients (94.3%) were initially diagnosed with stage III–IV disease and 44.3% had platinum-sensitive disease. Median progression-free survival in platinum-sensitive patients was 6.3 months [95% confidence interval (CI): 4.3–8.3] and 6.3 months (95% CI: 4.6–7.9) in platinum-resistant patients. Median overall survival was 15.8 months (95% CI: 13.6–18.1) in the platinum-sensitive patients and 18.4

months (95% CI: 10.0–27.8) in the platinum-resistant patients. Platinum-sensitive patients had a RR of 43.2% and platinum-resistant patients had a RR of 39.1%. The clinical benefit was 70.5% in platinum-sensitive patients and 65.2% in platinum-resistant patients. Overall treatment had a favorable safety profile. Gemcitabine and carboplatin demonstrate moderate toxicity with similar efficacy in both platinum-sensitive and platinum-resistant epithelial ovarian cancer, suggesting reversal of platinum resistance by c 2014 gemcitabine. Anti-Cancer Drugs 25:340–345  Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction

epirubicin [9], and taxanes [10,11]. However, the value of second-line therapy and its impact on survival is modest with a response rate (RR) of only 10–15% to further chemotherapy [12], and lengthy remissions are infrequent. As a result, the treatment of recurrent disease is an important aspect in the overall management of patients with ovarian cancer, and its goal is to palliate symptoms and to maintain quality of life.

Ovarian cancer is the fifth most common cause of cancer death in women [1]. Conventional therapy for ovarian cancer comprises surgical tumor cytoreduction followed by a combination of platinum-based and taxane-based chemotherapy, leading to a median survival of 38 months [2]. Despite that, patients relapse after achieving complete clinical response, and in the majority of these patients the disease is incurable [3,4]. The disease-free interval appears to be a significant predictor of further response to chemotherapy, with a better prognosis for patients who experience recurrence after more than 6 months from their last exposure to a platinum compound. Patients who relapse after less than 6 months are regarded as platinum resistant and are not considered suitable for platinum-containing regimens or secondary surgical cytoreduction [3]. Such patients are usually treated by non-platinum-based single-agent systemic chemotherapy such as topotecan [5], pegylated liposomal doxorubicin (PLD) [6], gemcitabine [7], etoposide [8], c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4973 

Anti-Cancer Drugs 2014, 25:340–345 Keywords: carboplatin, gemcitabine, recurrent epithelial ovarian cancer a Department of Oncology, Tel Aviv Sourasky Medical Center and bDepartment of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, Division of Gynecologic Oncology, Tel Aviv, Israel, both affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Correspondence to Tamar Safra, Department of Oncology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel Tel: + 972 3 6973494; fax: + 972 3 6974828, e-mail: [email protected] Received 16 July 2013 Revised form accepted 3 October 2013

Gemcitabine is a nucleoside pyrimidine analog that incorporates its triphosphate (dFdCTP) into DNA, and subsequently leads to inhibition of exonuclease and DNA repair [13]. Gemcitabine has been administered as a single agent in doses ranging between 800 and 1250 mg/m2 and has demonstrated RRs of 11–29% for treatment of recurrent ovarian cancer [7,14–18]. Specifically, a RR of 14–18% was achieved in platinum-resistant patients [19,20]. Preclinical models in an ovarian cancer cell line (A2780) have demonstrated synergistic activity of the combination of gemcitabine and cisplatin compared with DOI: 10.1097/CAD.0000000000000042

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Gemcitabine/carboplatin in ovarian cancer Safra et al.

either single agent [21,22]. It has been suggested that gemcitabine may directly inhibit repair of cisplatininduced intrastrand adducts and interstand crosslinks [23–25].

Treatment modifications

In view of the proposed synergistic mechanism of gemcitabine and carboplatin, the current study verified the efficacy of carboplatin–gemcitabine combination in platinum-sensitive and platinum-resistant epithelial ovarian cancer patients.

Assessment of safety and outcome

Patients and methods

341

The dose was modified by 20% upon significant adverse events and according to the treating physician’s discretion.

Toxicities were evaluated according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2. Toxicity evaluations and blood chemistry analyses were performed at the end of each cycle. Statistical methods

This is a retrospective study using the medical records of consecutive patients diagnosed and treated for epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma from 2005 through 2012 at the Tel Aviv Sourasky Medical Center. Institutional Review Boards and Cancer Center Research Review committee approval, as well as waivers of informed consent to use deidentified information, was obtained. The retrieved clinical data included patient’s age at diagnosis, stage of disease at diagnosis, tumor histology, tumor grade, ethnicity, patient and family cancer history, BRCA mutation status, comorbidities, surgical management, first-line chemotherapy, treatment toxicity, platinum sensitivity, progression-free survival (PFS), first platinum-free interval, overall survival (OS), and status at most recent follow-up.

All data were summarized and displayed as median, interquartile range (25–75th percentiles), and range for all continuous variables, and as number and percentage in each group for categorical variables. Univariate comparisons of potential prognostic factors (i.e. age at diagnosis, platinum sensitivity or resistance, etc.), with regard to OS and PFS were performed using the Mann–Whitney U statistics or the w2. Survival functions were demonstrated using the Kaplan–Meier method with comparison between the platinum-sensitive and the platinum-resistant patients using the log-rank analysis. In addition, multivariate survival analysis was done using the Cox proportional hazard models. All analyses were considered significant for P less than 0.05 (two-sided). All analyses were performed using the IBM SPSS software (version 21; IIBM Corporation, Armonk, New York, USA).

Treatment

Results

Carboplatin [area under the curve (AUC) = 5] was administered on day 1 and gemcitabine 850 mg/m2 was administered on days 1 and 8 in a 21-day cycle. All patients continued treatment with additional accepted agents for ovarian cancer (PLD, topotecan, taxanes, etoposide, etc.), though the platinum-resistant population was treated mainly with single agent and the platinum-sensitive population tended to receive more of the platinum–taxane and platinum–PLD combinations. Study endpoints

The primary endpoint of the study was PFS calculated from initiation of treatment with carboplatin and gemcitabine to progression, patient refusal, toxicity, death, or the last known follow-up. Secondary endpoints were OS calculated from the initiation of treatment with carboplatin and gemcitabine to either death or the last known follow-up, RR, clinical benefit, and safety. RR was defined as the composite of complete response (CR) and partial response (PR). Clinical benefit was defined as the composite of CR, PR, and stable disease. Definition of platinum resistance

Disease was considered to be platinum resistant if the patient had a documented response and developed recurrence or disease progression for less than 6 months after the end of front-line platinum-based chemotherapy.

Patient Characteristics

Patient characteristics are presented in Table 1. A total of 70 patients with a median age of 57 years (range: 38–86) were included in the efficacy analysis. Most patients (94.3%) were initially diagnosed with stage III–IV. Over half of the patients had serous papillary disease (55.7%) and 35.7% had endometrioid carcinoma. Thirty-one of 70 patients (44.3%) had platinum-sensitive disease. The median line of therapy was 3 (range: 2–7). A third of the patients (30%) tested positive for the BRCA mutation, and 42.9% tested negative for the mutation, while 27.1% of patients were not tested. Outcome

The RR and clinical benefit were similar in platinumresistant and platinum-sensitive patients. Platinumsensitive patients had an RR of 43.2% compared with an RR of 39.1% in platinum-resistant patients (P = 0.799). The clinical benefit was 70.5% in platinum-sensitive patients and 65.2% in platinum-resistant patients (P = 0.783, Table 2). Median PFS and OS were also similar in the platinumresistant and platinum-sensitive patient groups (Table 2). The median PFS of platinum-sensitive patients and platinum-resistant patients was 6.3 months [95% confidence interval (CI): 4.3–8.3; range 1–34.5 and 95% CI: 4.6–7.9; range: 0.9–26.8, respectively, P = 0.621] (Fig. 1).

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

342

Anti-Cancer Drugs 2014, Vol 25 No 3

The median OS was 15.8 months (95% CI: 13.6–18.1; range: 1–72.1) in the platinum-sensitive patient group and 18.4 months (95% CI: 10.0–27.8; range: 0.9–43.8) in the platinum-resistant patient group (P = 0.825) (Fig. 2).

and one patient, respectively. Grade 3–4 weakness was reported in 13 patients (18.6%).

Multivariate analysis using Cox regression adjusted for age at diagnosis, line of treatment, platinum sensitivity status, and BRCA status showed that age had a strong influence on PFS [for each 10-year increment, hazard ratio (HR) = 1.61, 95% CI: 1.57–1.65, P < 0.001]. In addition, platinum-resistant patients demonstrated a similar PFS (HR = 0.5, 95% CI: 0.24–1.05, P = 0.069). None of the other parameters had any significant influence on the PFS in our sample of patients.

Although platinum agents are still the most important drugs for treatment of ovarian cancer, many factors contribute to platinum resistance [26], preventing its use for treatment of recurrent disease.

Platinum sensitivity and BRCA status had no influence on OS (P = 0.973 and 0.286, respectively). Here, and similarly to PFS, older age was a risk factor for OS (for each 10-year increment, HR = 1.44, 95% CI: 1.40–1.48, P = 0.010). Administration of gemcitabine as third line had no influence on OS compared with second line, but patients who received it as fourth line or more had a significantly higher risk for mortality (HR = 2.6, 95% CI:1.2–5.8, P = 0.021) compared with second line.

Discussion

The therapeutic efficacy of cisplatin derives from its ability to form complexes with DNA [27], where it binds the N7 reactive center on purine residues to form both monofunctional and bifunctional DNA adducts. The 1,2intrastrand GG cross-link (65%) and the 1,2-intrastrand AG cross-link (25%) are the predominant lesions; minor lesions include the 1,3-intrastrand GNG cross-link (6%), the interstrand GG cross-link (1–3%), monoadducts, and protein-DNA cross-links [28]. Gemcitabine (20 ,20 -difluorodeoxycytidine) is a nucleoside analog. Upon entering the cell, gemcitabine is anabolized to its triphosphate form by Fig. 1

100

Safety

Table 1

Patient characteristics Patients (N = 70) [N (%)]

Median age (range) (years) Stage II III/IV Histology Serous Endometrioid Other Platinum sensitive BRCA status Negative Positive Unknown Line of Rx Second Third Fourth Fifth or more

Table 2

57 (38–86) 4 (5.7) 66 (94.3) 39 25 6 31

Platinum resistant Platinum sensitive 80 Progression-free survival (%)

Overall treatment had a favorable safety profile (Table 3). Most toxicity was grade 1 or 2. Grade 3–4 neutropenia was reported in four patients (5.7%) and grade 3–4 anemia and thrombocytopenia were reported in only two

(44.3) (21.4) (18.6) (15.7)

40

20

(55.7) (35.7) (8.6) (44.3)

0

30 (42.9) 21 (30.0) 19 (27.1) 31 15 13 11

60

0

10

30 20 Follow-up (months)

40

50

Time to progression: there was no difference between the platinumsensitive and platinum-resistant patients (log-rank P = 0.621).

Prognosis for platinum-sensitive and platinum-resistant patients Total

Response rate [N (%)] Clinical benefit [N (%)] PFS (median) (95% CI) OS (median) (95% CI)

28 46 6.3 16.6

(41.8) (68.7) (4.7–7.9) (13.9–19.3)

Platinum sensitive

Platinum resistant

19 31 6.3 15.8

9 15 6.3 18.4

(43.2) (70.5) (4.3–8.3) (13.6–18.1)

(39.1) (65.2) (4.6–7.9) (10.0–27.8)

P value 0.799 0.783 0.621 0.825

CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Gemcitabine/carboplatin in ovarian cancer Safra et al.

Fig. 2

100

Platinum resistant Platinum sensitive

Overall survival (%)

80

60

40

20

0 0

20

40 60 Follow-up (months)

50

Overall survival: there was no difference between the platinum-sensitive and platinum-resistant patients (log-rank P = 0.825).

Table 3

Toxicity profile Number of patients (N = 70)

Toxicity Hematologic Neutropenia Anemia Thrombocytopenia Nonhematologic Nausea Vomiting Weakness Diarrhea Hair loss Urticaria Lack of appetite Dyspnea Ankle edema

Grade 1

Grade 2

Grade Z 3

26 (37.1) 22 (31.4) 6 (8.6)

22 (31.4) 32 (45.7) 8 (11.4)

4 (5.8) 2 (2.9) 1 (1.4)

31 34 20 8 4 13 31 14 6

2 2 18 2 1 2 3

– – 8 (11.4) – – – – – –

(44.3) (48.6) (28.6) (11.4) (5.7) (18.6) (44.3) (20.0) (8.6)

(2.9) (2.9) (25.7) (2.9) (1.4) (2.9) (4.3) – –

deoxynucleoside salvage pathways. The triphosphate can then become incorporated into DNA, where it blocks further DNA synthesis by inhibiting DNA polymerase activity [29]. Gemcitabine also inhibits ribonucleotide reductase (RNR), hence depleting the deoxynucleotide pools required for DNA repair and replication, and thereby potentiating its incorporation into newly synthesized DNA [30]. Cisplatin and gemcitabine are ideal candidates for use in combination regimens because of their different but complementary mechanisms of action, similar antitumor activity profiles, and non-overlapping side effect profiles [31]. The synergistic interaction between these

343

drugs may be because of the inhibitory effect of gemcitabine on the repair of the major cytotoxic lesions induced by cisplatin [25]. Several studies have shown the synergistic activity of platinum agents/salts and gemcitabine [24,25,32–35]. Combinations of platinum salts/agents and gemcitabine were administered to ovarian cancer patients in various doses and time schedules. Administration of gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin (AUC) 4 mg/ml/min on day 1 to platinum-sensitive ovarian cancer patients led to a RR of 47.2% and significantly improved median PFS of 8.6 months (95% CI: 7.9–9.7 months) compared with a median PFS of 5.8 months (95% CI: 5.2–7.1 months) in patients who received carboplatin alone (AUC 5 on day 1, P = 0.0038) [34]. Efficacy was also observed in platinum-resistant patients. Treatment of 27 recurrent platinum-resistant and platinum-sensitive ovarian cancer patients with gemcitabine 600–750 mg/m2 plus cisplatin 30 mg/m2 on days 1 and 8 in a 21-day cycle yielded a RR of 70% (CR of 24% and PR of 44%) and PFS of 7.9 months. The objective RR for the platinum-resistant patients was 57% and the platinumfree interval was 8 months (range: 3–16) [33]. In an additional study, treatment of recurrent platinum-resistant ovarian cancer patients with gemcitabine 750 mg/m2 plus cisplatin 30 mg/m2 for the same schedule led to an RR of 42.9% (CR of 11.4%, PR of 31.4% and stable disease of 25.4%). PFS was 6 months and OS was 12 months [35]. The same treatment in platinum-resistant patients given on a 28-day schedule yielded an objective RR of 16%, a PFS of 5.4 months, and an OS of 14.9 months [32]. However, the efficacy of carboplatin and gemcitabine in a platinum-resistant population has been less thoroughly investigated. The results of the current study showed that the combination of gemcitabine and carboplatin led to similar outcomes in terms of RR, PFS, and OS in patients with platinum resistance compared with platinum-sensitive patients. It is noteworthy that the efficacy was maximal when the carboplatin–gemcitabine combination was used as second or third line. Therefore, it should be considered early in the treatment of recurrent disease. Moreover, cytosine arabinoside exhibits a similar effect on platinum resistance (presumably driven by the inhibition of DNA polymerases alpha, beta, and delta), which has been known since the 1980s and may be further enhanced by the addition of hydroxyurea (an inhibitior of RNR) [36]. However, ara-C has rarely been used in clinical ovarian carcinomas apart from an intraperitoneal study [37], due to an unproven paradigm suggesting its inactivity in solid tumors. RNR overexpression is a potential gemcitabine resistance mechanism, and therefore RNR inhibition would be a way to enhance gemcitabine activity [38]. A sequence-dependent interaction between the RNR inhibitor triapine or hydroxyurea and gemcitabine has been shown to be beneficial.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

344 Anti-Cancer Drugs 2014, Vol 25 No 3

However, clinical studies of such a doublet (either triapine or hydroxyurea) did not advance beyond phase I [39]. It is noteworthy that the chemomodulating effect of gemcitabine on platinum resistance takes place even using a conventional day 1 + 8 q3w schedule with gemcitabine only at day 8. This may raise the question of the gemcitabine modulation of carboplatin resistance when it is not given simultaneously. This phenomenon could be explained by the ‘carry-over effect’ of gemcitabine described by Grimison et al. [40]. The current study supports several similar reports [24,32,35,41–44] that suggested induction of conversion of platinum resistance by gemcitabine, enabling patients with platinum-resistant disease to continue treatment with platinum agents and to have a similar outcome to that of platinum-sensitive patients. According to these data, there is enough preclinical evidence that platinum-resistant patients may be successfully retreated with platinum-based regimens, provided that platinum is combined with an effective chemomodulator (gemcitabine or ara-C). Furthermore, the limited toxicity of this combination allows patients to maintain their quality of life.

2 3

4

5

6

7

8

9

10

11

The increasing number of drugs now available has widened the choice of agents and possible combinations considerably. Although this is a retrospective study, our report shows that platinum-resistant patients with ovarian cancer may do as well as patients with platinum-sensitive disease in terms of both RR and survival, due to a pharmacology-based therapeutic approach. This can be achieved using individualized chemotherapy directed by a chemosensitivity assay [42,44].

12

The retrospective nature of this study may be both a weakness (since retrospective studies are normally lower ranged than prospective studies) and a strength (since it analyzes the clinical course of existing patients in clinical practice and not highly selected patient populations as normally recruited into prospective clinical trials). We were able to show that the combination of carboplatin and gemcitabine is similarly active in patients with platinumsensitive and platinum-refractory relapsed ovarian carcinoma. Moreover, we were able to suggest that gemcitabine might be able to reverse clinical platinum resistance. This may offer new platinum-based options for patients with overt platinum-resistant ovarian carcinoma, and should be further investigated in larger cohorts, hopefully resulting in the acceptance of gemcitabine–platinum combinations for the treatment of platinum-resistant ovarian carcinoma.

16

Acknowledgements

13

14

15

17 18

19

20

21

22

23

Conflicts of interest

There are no conflicts of interest.

References 1

American Cancer Society. Cancer facts and figures 2012. Atlanta: American Cancer Society; 2012.

24

25

NCCN. NCCN Guidelines 2. Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer. USA: NCCN; 2012. Mantia-Smaldone GM, Edwards RP, Vlad AM. Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies. Cancer Manag Res 2011; 3:25–38. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003; 21:3194–3200. ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997; 15:2183–2193. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19:3312–3322. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (20 ,20 -difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994; 86:1530–1533. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998; 16:405–410. Luck HJ, Du Bois A, Weber B, Pfisterer J, Goupil A, Kuhn W, et al. The integration of anthracyclines in the treatment of advanced ovarian cancer. Int J Gynecol Cancer 2001; 11 (Suppl 1):34–38. McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273–279. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1995; 332:1004–1014. Naumann RW, Coleman RL. Management strategies for recurrent platinumresistant ovarian cancer. Drugs 2011; 71:1397–1412. Heinemann V, Schulz L, Issels RD, Plunkett W. Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 1995; 22:11–18. Shapiro JD, Millward MJ, Rischin D, Michael M, Walcher V, Francis PA, Toner GC. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996; 63:89–93. Friedlander M, Millward MJ, Bell D, Bugat R, Harnett P, Moreno JA, et al. A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 1998; 9:1343–1345. Silver DF, Piver MS. Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum. Am J Clin Oncol 1999; 22:450–452. Von Minckwitz G, Bauknecht T, Visseren-Grul CM, Neijt JP. Phase II study of gemcitabine in ovarian cancer. Ann Oncol 1999; 10:853–855. Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25:2811–2818. Yoshino K, Hiramatsu K, Enomoto T, Fujita M, Ueda Y, Kimura T, et al. Salvage chemotherapy using gemcitabine for taxane/platinum-resistant recurrent ovarian cancer: a single institutional experience. Anticancer Res 2012; 32:4029–4033. Markman M, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J. Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer. Gynecol Oncol 2003; 90:593–596. Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995; 22:72–79. Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996; 2:521–530. Van Moorsel CJ, Pinedo HM, Veerman G, Bergman AM, Kuiper CM, Vermorken JB, et al. Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines. Br J Cancer 1999; 80:981–990. Ledermann JA, Gabra H, Jayson GC, Spanswick VJ, Rustin GJ, Jitlal M, et al. Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer. Clin Cancer Res 2010; 16:4899–4905. Moufarij MA, Phillips DR, Cullinane C. Gemcitabine potentiates cisplatin cytotoxicity and inhibits repair of cisplatin-DNA damage in ovarian cancer cell lines. Mol Pharmacol 2003; 63:862–869.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Gemcitabine/carboplatin in ovarian cancer Safra et al.

26 27 28 29 30

31 32

33

34

35

36

Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007; 63:12–31. Cohen SM, Lippard SJ. Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol 2001; 67:93–130. Eastman A. Reevaluation of interaction of cis-dichloro(ethylenediamine) platinum(II) with DNA. Biochemistry 1986; 25:3912–3915. Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer Drugs 1995; 6 (Suppl 6):7–13. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W. Inhibition of ribonucleotide reduction in CCRF-CEM cells by 20 ,20 difluorodeoxycytidine. Mol Pharmacol 1990; 38:567–572. Carmichael J. The role of gemcitabine in the treatment of other tumours. Br J Cancer 1998; 78 (Suppl 3):21–25. Brewer CA, Blessing JA, Nagourney RA, Morgan M, Hanjani P. Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2006; 103:446–450. Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 2003; 88:35–39. Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGOOVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006; 24:4699–4707. Rose PG, Mossbruger K, Fusco N, Smrekar M, Eaton S, Rodriguez M. Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Gynecol Oncol 2003; 88:17–21. Kurbacher CM, Bruckner HW, Andreotti PE, Kurbacher JA, Sass G, Krebs D. In vitro activity of titanocenedichloride versus cisplatin in four ovarian carcinoma

37

38

39

40

41

42

43

44

345

cell lines evaluated by a microtiter plate ATP bioluminescence assay. Anticancer Drugs 1995; 6:697–704. Markman M, Cleary S, Lucas WE, Howell SB. Intraperitoneal chemotherapy with high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity. J Clin Oncol 1985; 3:925–931. Muggia F, Diaz I, Peters GJ. Nucleoside and nucleobase analogs in cancer treatment: not only sapacitabine, but also gemcitabine. Expert Opin Investig Drugs 2012; 21:403–408. Traynor AM, Lee JW, Bayer GK, Tate JM, Thomas SP, Mazurczak M, et al. A phase II trial of triapine (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503. Invest New Drugs 2010; 28:91–97. Grimison P, Galettis P, Manners S, Jelinek M, Metharom E, de Souza PL, et al. Randomized crossover study evaluating the effect of gemcitabine infusion dose rate: evidence of auto-induction of gemcitabine accumulation. J Clin Oncol 2007; 25:5704–5709. Breidenbach M, Rein DT, Schondorf T, Schmidt T, Konig E, Valter M, Kurbacher CM. Hematological side-effect profiles of individualized chemotherapy regimen for recurrent ovarian cancer. Anticancer Drugs 2003; 14:341–346. Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, et al. Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 1998; 9:51–57. Cree IA, Kurbacher CM, Lamont A, Hindley AC, Love S. A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician’s choice in patients with recurrent platinumresistant ovarian cancer. Anticancer Drugs 2007; 18:1093–1101. Sharma S, Neale MH, Di Nicolantonio F, Knight LA, Whitehouse PA, Mercer SJ, et al. Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma. BMC Cancer 2003; 3:19.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients.

The aim of this study was to evaluate progression-free survival, overall survival (OS), response rate (RR), and clinical benefit in recurrent ovarian ...
353KB Sizes 0 Downloads 0 Views