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Future Oncology

Symposium Paper

Discussion: session 1 Jalid Sehouli*1, Josep M del Campo2 & Domenica Lorusso3 Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité University Hospital, Berlin, Germany 2 Gynecological, Head & Neck Cancer Division, Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain 3 Gynecologic Oncology Unit, Fondazione `IRCCS’ National Cancer Institute, Milan, Italy *Author for correspondence: Tel.: +49 30 450 564002 n [email protected] 1

Is this efficacy in partially platinum-sensitive patients observed at any relapse? Jalid Sehouli

It is important to understand that we are not treating a single disease as there are different tumor behaviors. In reality, an individual patient will experience more than one relapse and the clinical challenge is to interpret the most recent data regarding how to manage patients across the different treatment lines. A recent publication from the AGO and GINECO study groups reported data relating to secondto sixth-line therapy and its impact on survival, based on an exploratory retrospective ana­lysis of a prospectively collected database from three randomized, Phase III clinical trials in 1620 patients with recurrent ovarian cancer. The ana­lysis showed that, in general, most patients with recurrent ovarian cancer receive up to five treatment lines, with many patients experiencing long-term survival [1]. Relapse treatment improved progression-free survival and overall survival (OS) at the second to fourth recurrence, although treatment was rarely performed according to the standard of care [1]. Regarding the efficacy of trabectedin/pegylated liposomal doxorubicin (PLD), it is clear that there is no difference if patients are treated in second- or third-line, indicating that it is not a case of neither/nor but, importantly, a question of when is the treatment best placed in second-, thirdor even fourth-line therapy. While there are currently no randomized, Phase III trials evaluating trabectedin/PLD in third-line or later, data from Phase II trials highlight that trabectedin is efficacious, even in partially platinum-sensitive patients, as second-, third- or later treatment lines [2]. In summary, it appears that the efficacy of trabectedin/PLD in second-line can be translated to subsequent treatment lines. References 1.

Hanker LC, Loibl S, Burchardi N et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann. Oncol. 23, 2605–2612 (2012).

2.

Lorusso D, Malaguti P, Masciullo V et al. Phase II trial of trabectedin (T) in heavily pretreated recurrent ovarian cancer (ROC) patients. J. Clin. Oncol. 29(15 Suppl.), Abstract 5060 (2011).

What are the benefits of extending the platinum-free interval? Josep M del Campo

There is increasing interest in platinum-free interval (PFI) extension strategies. PFI is the most important predictive factor for response to platinum retreatment and the most important prognostic factor for progression-free survival and OS [1–3]. The recent classification of patient subgroups by PFI (≤4 weeks and 12 months) is important for defining specific therapeutic approaches [4]. Approximately 20% of patients will relapse in the 6–12-month period and these are considered to be partially platinum-sensitive patients [5]. In this clinical setting, the potential benefit of artificially prolonging the PFI has been evaluated in several studies [6], with data suggesting that extending the PFI may restore platinum sensitivity and lead to responses or stable disease with platinum retreatment, even in heavily pretreated patients [7]. In vitro studies have shown platinum resistance to be an unstable, inducible and, possibly, reversible phenomenon [8]. Platinum resistance increases after each exposure, probably due to the selection of only highly resistant cells that would be less likely to respond to subsequent platinum challenge [8]. The mechanisms for platinum resistance are complex and multifactorial. For example, cisplatin-treated ovarian cancer cells overexpress IL-6, and blocking IL-6 significantly sensitizes platinum-resistant ovarian cancer cells to cisplatin [9]. Trabectedin has demonstrated inhibitory activity against the production of inflammatory cytokines, such as IL-6, in ovarian cancer cells and tumor-associated macrophages [10]. 10.2217/FON.13.201 © 2013 Future Medicine Ltd

Future Oncol. (2013) 9(12 Suppl. 1), 25–27

Keywords ovarian cancer n partially platinum-sensitive n pegylated liposomal doxorubicin n trabectedin n

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ISSN 1479-6694

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Symposium Paper

Sehouli, del Campo & Lorusso

In terms of evaluating treatment options to extend the PFI among nonplatinum drugs, studies in patients with platinum-sensitive disease have shown advantages for PLD compared with paclitaxel [11] or topotecan [7]. PLD was included in NICE recommendations as a nonplatinum treatment option for partially platinum-sensitive disease [101]. More recently, in 2009, trabectedin/PLD was approved for the treatment of platinum-sensitive disease after the combination demonstrated superiority compared with PLD alone [12]. References 1.

Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol. Oncol. 36, 207–211 (1990).

chemotherapy. Crit. Rev. Oncol. Hematol. 64, 129–138 (2007). 8.

Horowitz NS, Hua J, Gibb RK, Mutch DG, Herzog TJ. The role of topotecan for extending the platinumfree interval in recurrent ovarian cancer: an in vitro model. Gynecol. Oncol. 94, 67–73 (2004). Cohen S, Bruchim I, Graiver D et al. Platinumresistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2. J. Mol. Med. 91, 357–368 (2013).

2.

MarkmanM, Rothman R, Hakes T et al. Secondline platinum therapy in patients with ovarian cancer previously treated with cisplatin. J. Clin. Oncol. 9, 389–393 (1991).

9.

3.

Pujade-Lauraine E, Paraiso D, Cure H et al. Predicting the effectiveness of chemotherapy (Cx) in patients with recurrent ovarian cancer (ROC): a GINECO study. Proc. Am. Soc. Clin. Oncol. 21, Abstract 829 (2002).

10. Allavena P, Signorelli M, Chieppa M et al. Anti-

Friedlander M, Trimble E, Tinker A et al. Clinical trials in recurrent ovarian cancer. Int. J. Gynecol. Cancer 21, 771–775 (2011).

11. O’Byrne KJ, Bliss P, Graham JD et al. A Phase III

4.

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du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory ana­lysis of 3 prospectively randomized Phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGOOVAR) and the Grouped’InvestigateursNationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 115, 1234–1244 (2009).

6.

Kaye S. Management of partially platinum-sensitive relapsed ovarian cancer. Eur. J. Cancer 6(Suppl.), 16–21 (2008).

7.

Colombo N, Gore M. Treatment of recurrent ovarian cancer relapsing 6–12 months post platinum-based

inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 65, 2964–2971 (2005). study of doxil/caylex versus paclitaxel in platinum treated taxane naive relapsed ovarian cancer. Proc. Am. Soc. Clin. Oncol. 21(203A), Abstract 808 (2002). 12. Poveda A, Vergote I, Tjulandin S et al. Trabectedin

plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinumsensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 Phase III randomized trial. Ann. Oncol. 22, 39–48 (2011).

Website 101. NICE. Paclitaxel, pegylated liposomal doxorubicin

hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer: technology appraisal 91 (2005). www.nice.org.uk/nicemedia/pdf/ta091guidance.pdf

What is the importance of the sequence of treatment? Domenica Lorusso

Since the early 1990s until recently, first-line treatment options for ovarian cancer have remained unchanged. In that time, the increase in OS for patients with ovarian cancer has largely been due to the treatment of recurrent disease (Figure 1). Despite approximately 80% ovarian cancer response rates to primary therapy, most women eventually experience recurrent disease [1]. During the course of their illness, patients may undergo multiple cycles of treatment, response and recurrence [2], and patients are treated over a continuum in which therapeutic choices and strategies may impact future therapies [2]. Thus, there is continued need for the development of new, effective agents for the management of recurrent ovarian cancer. In partially platinum-sensitive patients, the median OS reported in the OVA-301 study for trabectedin/PLD was 22.4 months [3]; however, when a subgroup of patients receiving platinum immediately after trabectedin/PLD was evaluated, the median OS increased to 27.7 months [4]. It is not yet clear whether this increase in median OS resulted from the delayed reintroduction of platinum, or whether it is related to the particular mechanism of action of trabectedin; ongoing randomized clinical trials will help to address these observations.

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Discussion: session 1

References

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Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J. Clin. Oncol. 28, 3107–3114 (2010). Bukowski RM, Ozols RF, Markman M. The management of recurrent ovarian cancer. Semin. Oncol. 34(2 Suppl. 2), S1–S15 (2007). Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival ana­lysis. Eur. J. Cancer 48, 2361–2368 (2012). Colombo N. Efficacy of trabectedin in platinumsensitive-relapsed ovarian cancer: new data from the randomized OVA-301 study. Int. J. Gynecol. Cancer 21(Suppl. 1), S12–S16 (2011).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Editorial assistance was provided by Content Ed Net, with funding from PharmaMar, Madrid, Spain.

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Survival rate (%)

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1990 Cisplatin

1993 Cisplatin Paclitaxel

1998 Carboplatin Paclitaxel

DFS

Survival from recurrence

2013 Platinum Paclitaxel Bevacizumab Overall survial

Figure 1. Rates of overall and disease-free survival, and survival from disease recurrence, in patients with ovarian cancer since the early 1990s. DFS: Disease-free survival.

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Discussion: session 1.

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