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Dose-dense therapy is of benefit in primary treatment of ovarian cancer: contra
Annals of Oncology 22 (Supplement 8): viii33–viii39, 2011 doi:10.1093/annonc/mdr514
symposium article Dose-dense therapy is of benefit in primary treatment of ovarian cancer: contra M. E. L. van der Burg*, I. A. Boere & P. M. J. J. Berns Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
introduction Cytoreductive surgery, upfront or after neoadjuvant chemotherapy, and six cycles of 3-weekly paclitaxel/carboplatin is the standard treatment for advanced epithelial ovarian cancer (EOC). With this standard treatment the median progressionfree survival (PFS) varies between 16 and 21 months and the median overall survival (OS) between 32 and 57 months [1–8]. The addition of a third cytotoxic agent to standard 3-weekly paclitaxel/carboplatin, in triplets or in sequential doublets, did not improve OS or PFS [9–11]. Although the response rate to standard paclitaxel/carboplatin is high, most patients still experience a recurrence and will finally die due to the disease. New strategies are needed to improve the outcome in advanced-stage ovarian cancer. In a retrospective analysis, Levin and Hryniuk [12] showed a positive relationship between clinical outcome and the dose intensity of standard first-line therapy. Several prospective randomized studies have *Correspondence to: Dr M. E. L. van der Burg, Department of Medical Oncology, Erasmus Medical Center Rotterdam, ‘s Gravendijkwal 230, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31-10-703-48-97; Fax: +31-10-703-46-27; E-mail: [email protected]
investigated the potential benefit of increased platinum dose intensity on the outcome of advanced ovarian cancer.
platinum dose intensity in first-line therapy increased platinum dose intensity per cycle Several studies have investigated the effect of an increased dose intensity of cisplatin or carboplatin in first-line therapy in advanced ovarian cancer (Table 1). Two studies increased the dose per cycle and one study only reduced the interval between the cycles while maintaining the same total cumulative dose (TCD) [13–15]. McGuire et al. [13] compared eight cycles of 3weekly cisplatin 50 mg/m2 and cyclophosphamide (CTX) 500 mg/m2 with four cycles of 3-weekly cisplatin 100 mg/m2 and CTX 1000 mg/m2, which resulted in a dose-intensity factor of 2, whereas Gore et al. [14] compared six cycles of 4-weekly carboplatin at an area under the curve (AUC) of 8 mgml/min with four cycles of 4-weekly carboplatin AUC 12, which reached a dose-intensity factor of 1.4. Wrigley et al. [15] reduced the interval between the cycles from 4 to 3 weeks. In these three studies, no benefit was found, OS was not improved and the
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Several studies in the past have tried to improve the prognosis of ovarian cancer by increasing the dose intensity of platinum. Only 2 out of 12 randomized studies showed survival benefit at the cost of significant long-term toxicity. Dose-dense induction therapy with combined weekly paclitaxel (at a dose of 90 mg/m2) and weekly carboplatin [at an area under the curve (AUC) of 4 mgml/min] followed by 3-weekly paclitaxel/carboplatin was very effective in platinumresistant patients (response 58%, progression-free survival 10 months). In first-line, however, no survival benefit was found with the same dose-dense weekly paclitaxel/carboplatin regimen over standard-dosed 3-weekly paclitaxel/ carboplatin in a randomized study. Very recently, the Japanese Gynecologic Oncology Group (JGOG) study no. 3016, randomizing patients in first-line between dose-dense weekly paclitaxel 80 mg/m2 plus 3-weekly carboplatin AUC 6 and 3-weekly paclitaxel/ carboplatin, showed a significant increase in progression-free survival (median 28 versus 17.2 months in the control arm; hazard ratio for progression, 0.71; 95% confidence interval, 0.58–0.88; P=0.0015). The 3-year overall survival was 72% versus 65% (P=0.03), respectively. The hematologic toxicity was substantial in both arms and substantially higher than observed with the weekly paclitaxel/carboplatin induction regimen. Many patients had treatment delays, dose reductions and stopped treatment prematurely. The JGOG 3016 study is the only dose-dense study with such a significant survival benefit. It is also the only doseintensity study performed in Asian patients. Genotypes and phenotypes are thought to represent important determinants of drug efficacy in ovarian cancer. Therefore, confirmatory studies with this JGOG regimen together with translational research are needed in both Caucasian and Asian patients. Key words: dose density, dose intensity, first-line therapy, epithelial ovarian cancer, weekly paclitaxel, weekly platinum
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Annals of Oncology
Table 1. Dose intensity of first-line therapy in patients with advanced epithelial ovarian cancer reached by increased dose of cisplatin Study
No. of Standard arm patients
McGuire et al., 1995 [13] 485 227
Wrigley et al., 1996 [15]
144
Joly et al., 2000 [16]
195
Dittrich et al., 2003 [17]
253
Conte et al., 1996 [18]
145
Jakobsen et al., 1997 [19] 222 Ngan et al., 1989 [20]
Kaye et al., 1996 [21, 22]
65
159
Cisplatin 50 mg/m2 + CTX 500 mg/m2q 3 weekly · 8 Carboplatin AUC 8 q 4 weekly · 6 Carboplatin 300 mg/m2 + CTX 600 mg/m2 q 4 weekly · 6 Cisplatin 100 mg/m2 + CTX 600 mg/m2 q 4 weekly · 6
Cisplatin 100 mg/m2 + CTX 1000 mg/m2q 3 weekly · 4 Carboplatin AUC 12 q 4 weekly · 4 Carboplatin 300 mg/m2 + CTX 600 mg/m2q 3 weekly · 6 Cisplatin 100 mg/m2 + CTX 300 mg/m2 + carboplatin 300 mg/m2 q 4 weekly · 6 2 Cisplatin 100 mg/m + CTX Cisplatin 100 mg/m2 + 600 mg/m2 q 3 weekly · 6 carboplatin 300 mg/m2 q 4 weekly · 6 Cisplatin 100 mg/m2 + CTX Cisplatin 50 mg/m2 + CTX 600 mg/m2 + 600 mg/m2 + 2 epidoxorubicin 60 mg/m q epidoxorubicin 60 mg/m2 q 4 weekly · 6 4 weekly · 6 Carboplatin AUC 8 + CTX Carboplatin AUC 4 + CTX 500 mg/m2 q 4 weekly · 6 500 mg/m2 q 4 weekly · 6 2 Cisplatin 120 mg/m2 + CTX Cisplatin 60 mg/m + CTX 600 mg/m2 q 3 weekly · 6 600 mg/m2 q 3 weekly · 6 Cisplatin 50 mg/m22 + CTX 750 mg/m2 q 3 weekly · 6
Cisplatin 100 mg/m2 + CTX 750 mg/m2 q 3 weekly · 6
DI factor Increased Increased TCD survival
Increased toxicity
2
No
No
Yes
1.4
No
No
Yes
1.3
No
No
No
1.6
Yes
No
Yes
1.6
Yes
No
Yes
2
Yes (2·)
No
Yes
1.9
Yes (2·)
No
Yes
2
Yes (2·)
2
Yes (2·)
Yes Yes; 3-year survival 60% versus 30% Yes Yes; 4.9-year survival 32.4% versus 26.6%
DI factor, dose-intensity factor; TCD, total cumulative dose; q, repeated; CTX, cyclophosphamide.
toxicity was significantly higher in the dose-intense arms, which resulted in significantly more treatment delays and/or dose reductions. Joly et al. [16] and Dittrich et al. [17] increased the platinum dose intensity by adding carboplatin 300 mg/m2 to cisplatin 100 mg/m2 (6 CTX); thus reaching a dose-intensity factor for platinum of 1.6, together with an increase in the TCD. However, no survival benefit was found, only increased toxicity. In four studies both the dose intensity per cycle and the TCD of platinum were doubled in combination with standard dose CTX 6 epidoxorubicin [18–22]. Only two of these four studies showed a benefit in OS [20–22]. However, Ngan et al. [20] included only 65 patients in a randomized study comparing the combination of CTX 600 mg/m2 with cisplatin 120 mg/m2 or 60 mg/m2. The 3-year survival was 60% with the high-dose regimen and 30% with the low-dose regimen at the cost of increased hematologic, renal and neurotoxicity. No long-term follow-up data of this study have been published. Kaye et al. [21, 22] compared CTX 750 mg/m2 combined with cisplatin 100 mg/m2 and 50 mg/m2. After a follow-up of 4.9 years, OS was increased from 27% to 32% with an overall relative death rate of 0.68 (P=0.043). It appeared, however, that the benefit of high-dose cisplatin was greatest during the first 2 years; the relative death rate after 2 years was 0.52 versus 1.30 after 4.9 years. Acute and late toxicity, which lasted for >4 years, were significantly higher in the high-dose group. The authors therefore recommended a lower cisplatin dose of 75 mg/m2 as providing the optimal balance between efficacy and toxicity.
viii34 | van der Burg et al.
increased dose intensity by weekly cisplatin administration An increase in the dose intensity can also be reached by reducing the interval between cycles (Table 2). In three studies weekly cisplatin was compared with standard 3-weekly cisplatin [23–25]. With the weekly regimen a two times higher dose intensity was reached with the same TCD. Bolis et al. [23] compared nine cycles of weekly cisplatin 50 mg/m2 with six cycles of 3-weekly CTX 750 mg/m2 plus cisplatin 75 mg/m2. Cocconi et al. [24] reported the results of six weekly versus six 3-weekly cycles of cisplatin (both at a dose of 100 mg/m2) followed by four cycles of doxorubicin and CTX in both arms. Fruscio et al. [25] compared nine weekly cycles of cisplatin 50 mg/m2 with six 3-weekly cycles of cisplatin 75 mg/m2. No significant differences in PFS or OS were observed between the dose-dense and control arms in the three studies, neither in the short term nor in the long term. The nonhematologic toxicity (especially ototoxicity), however, was substantial and significantly higher in the weekly arms.
dose-dense weekly platinum therapy in platinum-resistant patients In contrast to the negative outcome of dose-dense cisplatin in first-line therapy, weekly platinum combination therapy was shown to be highly effective in platinum-resistant disease (Table 3). Already in 1980, Piver et al. [26] found in 7 out of 10
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Gore et al., 1998 [14]
Experimental arm
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Table 2. Dose intensity of first-line therapy in patients with advanced epithelial ovarian cancer reached by weekly cycles Study
No. of Standard arm patients
Bolis 607 et al., 1997 [23] Fruscio 285 et al., 2011 [25] Cocconi 101 et al., 1999 [24]
Van der Burg 263 et al., 2009 [37]
Planned DI factor
Increased Increased TCD survival
Increased toxicity
Cisplatin 50 mg/m2 q 1 weekly 2 · 9 cycles
No
No
No
Cisplatin 50 mg/m2 q 1 weekly 2 · 9 cycles Cisplatin 100 mg/m2 q 1 2 weekly · 6 cycles followed by CTX doxorubicin · 4 cycles
No
No
No
No
No
No
No Yes Yes
No
No
Yes No
Yes Yes; PFS 10.8 months, P = 0.0015; 3-year OS 7%, P = 0.03
Paclitaxel 90 mg/m2 + Paclitaxel 1.03, cisplatin 1.9, cisplatin 70 mg/m2 or carboplatin 1.3 carboplatin AUC 4 on days 1, 8, 15 + 29, 36, 43 followed by paclitaxel 175 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 6 q 3 weekly · 3–6 cycles Paclitaxel 80 mg/m2 Paclitaxel 1.3, Paclitaxel 180 mg/m2 carboplatin 1.0 +carboplatin AUC 6 q 3 on days 1, 8 + 15 + weekly · ‡6 cycles carboplatin AUC 6 on day 1 q 3 weekly · ‡6 cycles
DI factor, dose-intensity factor; TCD, total cumulative dose; q, repeated.
patients who had become resistant to conventionally dosed platinum a response when using six weekly cycles of cisplatin at a dose of 1 mg/kg followed by 60 mg/m2 every 3 weeks. Dose-dense weekly induction therapy with cisplatin 70 mg/m2 in combination with daily oral etoposide or weekly paclitaxel thus reached a 1.9-fold increased dose intensity, resulted in response rates of, respectively, 46% and 65%; these values are substantially higher than the £10% responses with conventional platinum chemotherapy [27–29]. In these studies, the median PFS was 5 and 8 months and the median OS was 10 and 11 months, respectively. When 3-weekly paclitaxel/carboplatin was shown to be equally effective but less toxic than 3-weekly paclitaxel/cisplatin in first-line treatment [6–8], weekly paclitaxel was combined with weekly carboplatin to reduce toxicity [30]. In this latter study, six weekly cycles with paclitaxel 90 mg/m2 and carboplatin AUC 4 induction therapy were followed by six cycles of 3-weekly paclitaxel 175 mg/m2 and carboplatin AUC 6 [30]. The overall response rate in the platinum-resistant patients was 58%, whereas 77% of patients had disease control (response + stable disease). The median PFS was 10 months (range 1–21) and the median OS was 12 months (range 1–69). In an attempt to further increase the efficacy, the weekly regimen was continued for 18 weeks in three studies. Cadron et al. [31] used the regimen of paclitaxel 90 mg/m2 and carboplatin AUC 4 on days 1 and 8 repeated (q) 21 days for six cycles; Havrilesky et al. [32] used paclitaxel 80 mg/m2 and carboplatin AUC 2 on days 1, 8 and 15 q 28 days until progression, SAE or 8 cycles after CR; and Sharma et al. [33] used paclitaxel 70 mg/m2 and carboplatin AUC 3 on days 1, 8 and 15 q 28 days for six cycles. In platinum-resistant
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patients they found response rates of 25%–38%, with the median PFS ranging from 3.2 to 8.7 months and the median OS from 6.8 to 11.4 months. Two studies investigated dose-dense weekly paclitaxel 90 mg/m2 combined with 4-weekly carboplatin AUC 5 [34, 35]. Hoekstra et al. [34] found in 5 platinum-resistant patients a response in 60%, while Lortholary et al. [35] found a response rate of 38% and a PFS of 4.9 months in 51 patients.
dose-dense weekly paclitaxel/ carboplatin in first-line therapy The positive results with weekly paclitaxel/platinum induction therapy in platinum-resistant ovarian cancer were the basis for a randomized first-line trial in advanced disease [36]. In this trial, patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV ovarian cancer were randomized between induction therapy with six cycles weekly paclitaxel 90 mg/m2 and cisplatin 70 mg/m2 or carboplatin AUC 4 on days 1, 8 and 15 and days 29, 36 and 43 versus three cycles of standard 3-weekly paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 6. In both arms treatment was followed by three to six 3-weekly cycles paclitaxel/platinum. Paclitaxel/ cisplatin was administered in the first 105 patients, after which cisplatin was replaced by carboplatin. In total, 267 eligible patients were randomized. No difference in response, PFS or OS was observed between the dose-dense weekly and the standard 3-weekly regimens. The median PFS was 19 months in the
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Katsumata 631 et al., 2009 [38]
Cisplatin 75 mg/m2 + CTX 750 mg/m2 q 3 weekly · 6 cycles Cisplatin 75 mg/m2 q 3 weekly · 6 cycles Cisplatin 100 mg/m2 q 3 weekly · 6 cycles followed by CTX doxorubicin · 4 cycles Paclitaxel 175 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 6 q 3 weekly · 6–9 cycles
Experimental arm
Study
Regimen
Platinum sensitivity
N (evaluable)
Van der Burg et al.,2005 [30]
P 90 mg/m2 + C AUC 4 on days 1, 8, 15 + 29, 35, 42 followed by PC q 3 weekly · 6 cycles P 90 mg/m2 + C AUC 4 on days 1 + 8 q 3 weekly · 6 cycles
All <6 months 6–12 months >12 months
62 23 19 20
All <6 months 6–12 months >12 months All <6 months >6 months
33 (29) 8 11 10 29 8 21
All Refractory <6 months >6 months All <6 months 6–12 months >12 months <6 months <6 months <6 months
21 5 7 9 20 5 5 10 57 51 57
Cadron et al., 2007 [31]
Havrilesky et al., 2003 [32]
Sharma et al., 2009 [33]
Hoekstra et al., 2009 [34]
Lortholary et al., 2011 [35]
CR (%)
PFS (months)
OS (months)
Toxicity Grade 3/4 % of patients Anemia Neutropenia Thrombocytopenia
Neurotoxicity
Hypersensitivity
64 64 89 79
10 14 47 16
11 10 12 11
20 14 29+ 32+
23
92
42
0
20
66 38 73 80 83 38 100
21 13 18 30 55 13 71
9 6.8 10.5 12.8 11.5 3.2 13.7
18 8 NR NR NR 11.4 NR
24
94
25
3
9
11
32
14
0
21
60 25 25 50 85 60 93
0
13.3 6.8 – 10.0 NR
5
30
0
14
14
75 40 87
7.9 8.9 5.5 7.8 –
0
35
0
0
25
35 38 39
14 5 10
3.7 4.8 5.4
19,9 15.2 19.9
6 19 27
13 54 42
447
32 20 30
2 16 7
N, number of patients; RR, response rate; CR, complete remission; PFS, progression-free survival; PD, progressive disease; NR, not reached; OS, overall survival; q, repeated; P, paclitaxel; C, carboplatin.
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P 80 mg/m2 + C AUC 2 on days 1, 8 + 15 q 4 weekly until PD/CR P 70 mg/m2 + C AUC 3 on days 1, 8 + 15 q 4 weekly · 6 cycles P 80 mg/m2 on days 1, 8 + 15 + C AUC 5 on day 1 q 4 weeks (a) P 80 mg/m2 on days 1, 8 + 15 (b) P 80 mg/m2 on days 1, 8 + 15 + C AUC 5 on day 1 (c) P 80 mg/m2 + topotecan 3 mg/m2 on days 1, 8 + 15 all regimens q 4 weekly
RR (%)
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Table 3. Dose-dense weekly paclitaxel + carboplatin in platinum-resistant progressive ovarian cancer
Annals of Oncology
discussion The intriguing results of the JGOG dose-dense study with weekly paclitaxel 80 mg/m2 on days 1, 8 and 15 combined with 3-weekly carboplatin AUC 6 are promising [37]. The median PFS for the dose-dense weekly paclitaxel/carboplatin regimen was 28 months, a significant improvement of 11 months compared with the standard 3-weekly paclitaxel 180 mg/m2 and carboplatin AUC 6. The 3-year OS rate was increased from 65% in the standard group to 72% in the dose-dense weekly group. These results, however, are in sharp contrast with the phase III results of other dose-intensity studies with cisplatin, carboplatin and weekly paclitaxel/platinum induction therapy (Table 1 and Table 2). Only two of the previously performed 12 dose-intense platinum studies, both with an increased cisplatin dose per cycle and an increased cumulative platinum dose, showed a survival benefit at the cost of important long-lasting toxicity, which hampered the further development of doseintense cisplatin [20–22]. No survival benefit was seen in the three studies with weekly cisplatin [23–25]. It is not clear why such a large difference exists between the JGOG study with weekly paclitaxel and 3-weekly carboplatin, and the study with weekly paclitaxel/platinum induction therapy. Despite the considerably higher hematologic toxicity, leading to frequent
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dose reductions, treatment delays and premature therapy discontinuation, and the relatively low response rate in the JGOG study, the PFS and OS are considerably longer in the dose-dense weekly paclitaxel plus 3-weekly carboplatin group of the JGOG study. Some investigators suggested that a more prolonged administration of weekly paclitaxel/carboplatin would be more efficacious than only using weekly induction therapy followed by the 3-weekly cycles. This weekly induction regimen followed by 3-weekly paclitaxel/carboplatin cycles, however, has proved to be very effective in platinum-resistant patients with a response rate of 58% and a median PFS of 10 months, and seems to be at least as effective as continuation of weekly paclitaxel/carboplatin for six cycles in platinum-resistant patients [31, 32] (Table 3). Also, there is no evidence that the regimen with weekly paclitaxel combined with 4-weekly carboplatin is more efficacious in platinum-resistant patients [34, 35]. In the phase II study with paclitaxel 80 mg/m2 on days 1, 8 and 15 and carboplatin AUC 5 on day 1 every 4 weeks for six cycles, the response rate was 38% and the PFS was only 5 months in contrast to the 10 months with weekly paclitaxel/carboplatin induction therapy. A difference between these phase II regimens and the JGOG study is a gap of 1 week in the paclitaxel administration per cycle. Although in the JGOG study no gap between the paclitaxel administrations was planned, treatment delays occurred frequently as a result of the hematologic toxicity. Not only in the JGOG dose-dense weekly group but also in the control arm of that study (the standard 3-weekly paclitaxel/ carboplatin group), severe myelosuppression was leading more to treatment delays, dose reductions and premature treatment discontinuations than observed when using standard 3-weekly paclitaxel/carboplatin therapy in the Caucasian patients. This suggests that Asian patients may be more susceptible to the toxicity of paclitaxel/carboplatin-containing treatment regimens and that their tumor cells seem to be more sensitive to paclitaxel/carboplatin. Phan et al. [38] reported a reduced drug clearance with increased toxicity and Soo at al. [39] found in a meta-analysis an increase in OS in Asian patients and a higher response rate in Asian non-small-cell lung cancer patients receiving carboplatin/paclitaxel. Genotypes and phenotypes are thought to represent important determinants of drug efficacy in ovarian cancer [40–44]. Especially, a silent polymorphism at codon 118 in the DNA repair gene excision repair cross complementation group 1 (ERCC1) was shown to be an independent predictor for better survival in patients with advanced EOC treated with intravenous paclitaxel/carboplatin-based chemotherapy [41]. Previously, the same authors showed in EOC patients with minimal residual disease treated with intraperitoneal paclitaxel/ cisplatin, a relationship between polymorphism C8092A in the 3# untranslated region of ERCC1 and survival, while codon 118, i.e. C118T, was not significant [42]. Moreover, preliminary evidence suggests that ethnic differences in the expression of allelic variants, e.g. the allele frequency of ERCC1 C and T is 70% versus 30% in Asians and 40% versus 60% in Caucasians, may result in altered pharmacokinetics and pharmacodynamics of anticancer drugs [43, 44].
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dose-dense weekly group and 18 months (P = 0.64) in the standard 3-weekly group, and the median OS was 44 and 43 months (P=0.86), respectively. The Japanese Gynecologic Oncology Group (JGOG trial no. 3016), on the contrary, showed a significant benefit in both PFS and OS in favor of the dose-dense regimen [37]. In this study, 631 eligible patients with FIGO stages II–IV disease were randomized between weekly dose-dense paclitaxel 80 mg/m2 on days 1, 8 and 15 combined with 3-weekly carboplatin AUC 6, versus standard 3-weekly paclitaxel 180 mg/m2 and carboplatin AUC 6. The median PFS and the 3-year OS were significantly longer in the dose-dense group: PFS was 28 months in the dose-dense group versus 17 months in the standard group (hazard ratio for progression, 0.71; 95% confidence interval, 0.58–0.88; P=0.0015); and the 3-year OS rate was 72% versus 65% (P=0.03), respectively. The response rate in the weekly dose-dense group was 56% compared with 53% in the 3-weekly standard group. More toxicity was observed in the weekly dose-dense group; 53% of patients in the dose-dense group but also 37% of the patients in the standard 3-weekly group stopped treatment prematurely. The main reason for discontinuing treatment was hematologic toxicity. Grade 3/4 neutropenia was observed in 92% and 80% of the patients and thrombocytopenia in 44% and 38%, respectively. In the randomized study with weekly paclitaxel/platinum induction therapy, on the contrary, 15% of patients in the dose-dense regimen and 16% in the standard 3weekly group stopped treatment prematurely [36]. Hematologic toxicity was considerably less compared with what was observed in the JGOG study; grade 3/4 neutropenia was observed in only 44% of the patients in the dose-dense group and in 32% in the standard group, whereas grade 3/4 thrombocytopenia was observed in only 12% and 5% in both groups, respectively.
symposium article
symposium article conclusion
disclosures The authors declare no conflict of interest.
references 1. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6. 2. Piccart MJ, Bertelsen K, James K et al. Randomized intergroup trial of cisplatin– paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699–708. 3. Piccart MJ, Bertelsen K, Stuart G et al. Long-term follow-up confirms a survival advantage of the paclitaxel–cisplatin regimen over the cyclophosphamide– cisplatin combination in advanced ovarian cancer. Int J Gynecol Cancer 2003; 13 (Suppl 2)): 144–148. 4. Vergote I, Trope´ CG, Amant F et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943–953. 5. Van der Burg MEL, van Lent M, Buyse M et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995; 332: 629–634. 6. Neijt JP, Engelholm SA, Tuxen MK et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000; 18: 3084–3092. 7. Du Bois A, Luck HJ, Meier W et al. A randomized clinical trial of cisplatin/ paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–1329. 8. Ozols RF, Bundy BN, Greer BE 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. 9. Kristensen GB, Vergote I, Stuart G et al. First-line treatment of ovarian cancer FIGO stages IIb–IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/ carboplatin. Int J Gynecol Cancer 2003; 13 (Suppl 20)): 172–177. 10. Bolis G, Scarfone G, Raspagliesi F et al. Paclitaxel/carboplatin versus topotecan/ paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III–IV epithelial ovarian cancer a multicenter, randomized study. Eur J Cancer 2010; 46: 2905–2912. 11. Bookman MA, Brady MF, McGuire WP et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer InterGroup. J Clin Oncol 2009; 27: 1419–1425. 12. Levin L, Hryniuk WM. Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 1987; 5: 756–767.
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13. McGuire WP, Hoskins WJ, Brady MF et al. Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 1995; 13: 1589–1599. 14. Gore M, Mainwaring P, A’Hern R et al. Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. J Clin Oncol 1998; 16: 2426–2434. 15. Wrigley E, Weaver A, Jayson G et al. A randomized trial investigating the dose intensity of primary chemotherapy in patients with ovarian carcinoma: a comparison of chemotherapy given every four weeks with the same chemotherapy given at three-week intervals. Ann Oncol 1996; 7: 705–711. 16. Joly F, He´ron JF, Kerbrat P et al. High-dose platinum versus standard dose in advanced ovarian carcinoma: a randomized trial from the Gynecologic Cooperative Group of the French Comprehensive Cancer Centers (FNCLCC). Gynecol Oncol 2000; 78: 361–368. 17. Dittrich C, Sevelda P, Salzer H . Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomised phase III study comparing carboplatin–cisplatin with cyclophosphamide–cisplatin [erratum appears in Eur J Cancer 2004; 40: 627]. Eur J Cancer 2003; 39: 1129–1240. 18. Conte PF, Bruzzone M, Carnino F et al. High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ovest. J Clin Oncol 1996; 14: 351–356. 19. Jakobsen A, Bertelsen K, Andersen JE et al. Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study. J Clin Oncol 1997; 15: 193–198. 20. Ngan HY, Choo YC, Cheung M et al. A randomized study of high-dose versus low-dose cis-platinum combined with cyclophosphamide in the treatment of advanced ovarian cancer. Hong Kong Ovarian Carcinoma Study Group. Chemotherapy 1989; 35: 221–227. 21. Kaye SB, Paul J, Cassidy J et al. Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group. J Clin Oncol 1996; 14: 2113–2119. 22. Kaye SB, Lewis CR, Paul J et al. Randomised study of two doses of cisplatin with cyclophosphamide in epithelial ovarian cancer. Lancet 1992; 340: 329–333. 23. Bolis G, Favalli G, Danese S et al. Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 1997; 15: 1938–1944. 24. Cocconi G, Bella M, Lottici et al. Mature results of a prospective randomized trial comparing a three-weekly with an accelerated weekly schedule of cisplatin in advanced ovarian carcinoma. Am J Clin Oncol 1999; 22: 559–567. 25. Fruscio R, Garbi A, Parma G et al. Randomized phase III clinical trial evaluating weekly cisplatin for advanced epithelial ovarian cancer. J Natl Cancer Inst 2011; 103: 347–351. 26. Piver MS, Lele S, Barlow J. Weekly cis-diamminedichloroplatinum (II): active third-line chemotherapy in ovarian cancer—a preliminary report. Cancer Treat Rep 1980; 64: 1379–1382. 27. Van der Burg MEL, de Wit R, van Putten WLJ et al. Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer. Br J Cancer 2002; 86: 19–25. 28. De Jongh FE, de Wit R, Verweij J et al. Dose-dense cisplatin paclitaxel: a welltolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer. Eur J Cancer 2002; 38: 2005–2013. 29. Du Bois A. Treatment of advanced ovarian cancer. Eur J Cancer 2001; 37: S1–7. 30. Van der Burg MEL, van der Gaast A, Vergote I et al. What is the role of dosedense therapy? Int J Gyn Cancer 2005; 15 (Suppl 3)): 233–240. 31. Cadron I, Leunen K, Amant F et al. The ‘Leuven’ dose-dense paclitaxel/ carboplatin regimen in patients with recurrent ovarian cancer. Gynecol Oncol 2007; 106: 354–361. 32. Havrilesky LJ, Alvarez AA, Sayer RA et al. Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 2003; 88: 51–57. 33. Sharma R, Graham J, Mitchell H et al. Extended weekly dose-dense paclitaxel/ carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer. Br J Cancer 2009; 100: 707–712.
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Only one (i.e. JGOG 3016) out of a total of 14 randomized dose-intensity studies in first-line therapy using weekly paclitaxel combined with 3-weekly carboplatin, and in fact the only study performed in Asian patients, showed a large difference in PFS and OS despite significant hematologic toxicity leading to dose reductions, treatment delays and premature discontinuation of treatment. Confirmatory studies with the JGOG regimen with well defined translational research are urgently needed. These studies should include Caucasian as well as Asian patients and should be stratified for tumor histotype as suggested in the recent The Cancer Genome Alas (TCGA) study [43]. Prospective pharmacogenetic analyses of the tumor i.e. single nucleotide polymorphisms in DNA repair pathways within tumor histotypes might aid in the clarification of the pharmacokinetic and pharmacodynamic impact of this schedule. It also gives more insight in the underlying molecular processes within ethnic subgroups of patients.
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39. Soo RA, Loh M, Mok TS et al. Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials. J Thorac Oncol 2011; 6: 1030–1038. 40. Smith S, Su D, Rigault de la Longrais IA et al. ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. J Clin Oncol 2007; 33: 5172–5179. 41. Krivak TC, Darcy KM, Tian C et al. Single nucleotide polymorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study. Gyn Oncol 2011; 122: 121–126. 42. Krivak TC, Darcy KM, Tian C et al. Relationship between ERCC1 polymorphisms, disease progression, and survival in the Gynecologic Oncology Group phase III trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian cancer. J Clin Oncol 2008; 20: 3598–3606. 43. O’Donnell PH, Gamazon E, Zhang W et al. Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants. Pharmacogenetics Genomics 2010; 20: 327–337. 44. Bell D, Berchuch A, Birrer M et al. Integrated genomic analyses of ovarian carcinoma. Cancer Genome Atlas Research Network. Nature 2011; 474: 609–615doi:10.1038/nature10166.
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34. Hoekstra AV, Hurteau JA, Kirschner CV et al. The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer. Gynecol Oncol 2009; 115: 377–381. 35. Lortholary A, Largillier R, Weber B et al. Weekly paclitaxel as a single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from GINECO. Ann Oncol 2011 May 11 [epub ahead of print]. doi:10.1093/annonc/mdr149. 36. Van der Burg ME, Janssen JT, Ottevanger PB et al. Multicenter randomized phase III trial of 3-weekly paclitaxel/platinum (PC3w) versus weekly paclitaxel/platinum (PCw) induction therapy followed by PC3w maintenance therapy in advanced epithelial ovarian cancer (EOC). J Clin Oncol 2009; 27: 15s (Suppl 286s); Abstr 5538. 37. Katsumata N, Yasuda M, Takahashi F et al. Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–1338. 38. Phan VH, Tan C, Vardy JL et al. The role of gender in predicting for reduced drug clearance and increased toxicity in non-small cell lung cancer (NSCLC) patients receiving carboplatin and paclitaxel. J Clin Oncol 2011 29 (Suppl): 490 Abstr 7557.
symposium article
symposium article Dose-dense therapy is of benefit in primary treatment of ovarian cancer: contra M. E. L. van der Burg*, I. A. Boere & P. M. J. J. Berns Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
introduction Cytoreductive surgery, upfront or after neoadjuvant chemotherapy, and six cycles of 3-weekly paclitaxel/carboplatin is the standard treatment for advanced epithelial ovarian cancer (EOC). With this standard treatment the median progressionfree survival (PFS) varies between 16 and 21 months and the median overall survival (OS) between 32 and 57 months [1–8]. The addition of a third cytotoxic agent to standard 3-weekly paclitaxel/carboplatin, in triplets or in sequential doublets, did not improve OS or PFS [9–11]. Although the response rate to standard paclitaxel/carboplatin is high, most patients still experience a recurrence and will finally die due to the disease. New strategies are needed to improve the outcome in advanced-stage ovarian cancer. In a retrospective analysis, Levin and Hryniuk [12] showed a positive relationship between clinical outcome and the dose intensity of standard first-line therapy. Several prospective randomized studies have *Correspondence to: Dr M. E. L. van der Burg, Department of Medical Oncology, Erasmus Medical Center Rotterdam, ‘s Gravendijkwal 230, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel: +31-10-703-48-97; Fax: +31-10-703-46-27; E-mail: [email protected]
investigated the potential benefit of increased platinum dose intensity on the outcome of advanced ovarian cancer.
platinum dose intensity in first-line therapy increased platinum dose intensity per cycle Several studies have investigated the effect of an increased dose intensity of cisplatin or carboplatin in first-line therapy in advanced ovarian cancer (Table 1). Two studies increased the dose per cycle and one study only reduced the interval between the cycles while maintaining the same total cumulative dose (TCD) [13–15]. McGuire et al. [13] compared eight cycles of 3weekly cisplatin 50 mg/m2 and cyclophosphamide (CTX) 500 mg/m2 with four cycles of 3-weekly cisplatin 100 mg/m2 and CTX 1000 mg/m2, which resulted in a dose-intensity factor of 2, whereas Gore et al. [14] compared six cycles of 4-weekly carboplatin at an area under the curve (AUC) of 8 mgml/min with four cycles of 4-weekly carboplatin AUC 12, which reached a dose-intensity factor of 1.4. Wrigley et al. [15] reduced the interval between the cycles from 4 to 3 weeks. In these three studies, no benefit was found, OS was not improved and the
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Several studies in the past have tried to improve the prognosis of ovarian cancer by increasing the dose intensity of platinum. Only 2 out of 12 randomized studies showed survival benefit at the cost of significant long-term toxicity. Dose-dense induction therapy with combined weekly paclitaxel (at a dose of 90 mg/m2) and weekly carboplatin [at an area under the curve (AUC) of 4 mgml/min] followed by 3-weekly paclitaxel/carboplatin was very effective in platinumresistant patients (response 58%, progression-free survival 10 months). In first-line, however, no survival benefit was found with the same dose-dense weekly paclitaxel/carboplatin regimen over standard-dosed 3-weekly paclitaxel/ carboplatin in a randomized study. Very recently, the Japanese Gynecologic Oncology Group (JGOG) study no. 3016, randomizing patients in first-line between dose-dense weekly paclitaxel 80 mg/m2 plus 3-weekly carboplatin AUC 6 and 3-weekly paclitaxel/ carboplatin, showed a significant increase in progression-free survival (median 28 versus 17.2 months in the control arm; hazard ratio for progression, 0.71; 95% confidence interval, 0.58–0.88; P=0.0015). The 3-year overall survival was 72% versus 65% (P=0.03), respectively. The hematologic toxicity was substantial in both arms and substantially higher than observed with the weekly paclitaxel/carboplatin induction regimen. Many patients had treatment delays, dose reductions and stopped treatment prematurely. The JGOG 3016 study is the only dose-dense study with such a significant survival benefit. It is also the only doseintensity study performed in Asian patients. Genotypes and phenotypes are thought to represent important determinants of drug efficacy in ovarian cancer. Therefore, confirmatory studies with this JGOG regimen together with translational research are needed in both Caucasian and Asian patients. Key words: dose density, dose intensity, first-line therapy, epithelial ovarian cancer, weekly paclitaxel, weekly platinum
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Annals of Oncology
Table 1. Dose intensity of first-line therapy in patients with advanced epithelial ovarian cancer reached by increased dose of cisplatin Study
No. of Standard arm patients
McGuire et al., 1995 [13] 485 227
Wrigley et al., 1996 [15]
144
Joly et al., 2000 [16]
195
Dittrich et al., 2003 [17]
253
Conte et al., 1996 [18]
145
Jakobsen et al., 1997 [19] 222 Ngan et al., 1989 [20]
Kaye et al., 1996 [21, 22]
65
159
Cisplatin 50 mg/m2 + CTX 500 mg/m2q 3 weekly · 8 Carboplatin AUC 8 q 4 weekly · 6 Carboplatin 300 mg/m2 + CTX 600 mg/m2 q 4 weekly · 6 Cisplatin 100 mg/m2 + CTX 600 mg/m2 q 4 weekly · 6
Cisplatin 100 mg/m2 + CTX 1000 mg/m2q 3 weekly · 4 Carboplatin AUC 12 q 4 weekly · 4 Carboplatin 300 mg/m2 + CTX 600 mg/m2q 3 weekly · 6 Cisplatin 100 mg/m2 + CTX 300 mg/m2 + carboplatin 300 mg/m2 q 4 weekly · 6 2 Cisplatin 100 mg/m + CTX Cisplatin 100 mg/m2 + 600 mg/m2 q 3 weekly · 6 carboplatin 300 mg/m2 q 4 weekly · 6 Cisplatin 100 mg/m2 + CTX Cisplatin 50 mg/m2 + CTX 600 mg/m2 + 600 mg/m2 + 2 epidoxorubicin 60 mg/m q epidoxorubicin 60 mg/m2 q 4 weekly · 6 4 weekly · 6 Carboplatin AUC 8 + CTX Carboplatin AUC 4 + CTX 500 mg/m2 q 4 weekly · 6 500 mg/m2 q 4 weekly · 6 2 Cisplatin 120 mg/m2 + CTX Cisplatin 60 mg/m + CTX 600 mg/m2 q 3 weekly · 6 600 mg/m2 q 3 weekly · 6 Cisplatin 50 mg/m22 + CTX 750 mg/m2 q 3 weekly · 6
Cisplatin 100 mg/m2 + CTX 750 mg/m2 q 3 weekly · 6
DI factor Increased Increased TCD survival
Increased toxicity
2
No
No
Yes
1.4
No
No
Yes
1.3
No
No
No
1.6
Yes
No
Yes
1.6
Yes
No
Yes
2
Yes (2·)
No
Yes
1.9
Yes (2·)
No
Yes
2
Yes (2·)
2
Yes (2·)
Yes Yes; 3-year survival 60% versus 30% Yes Yes; 4.9-year survival 32.4% versus 26.6%
DI factor, dose-intensity factor; TCD, total cumulative dose; q, repeated; CTX, cyclophosphamide.
toxicity was significantly higher in the dose-intense arms, which resulted in significantly more treatment delays and/or dose reductions. Joly et al. [16] and Dittrich et al. [17] increased the platinum dose intensity by adding carboplatin 300 mg/m2 to cisplatin 100 mg/m2 (6 CTX); thus reaching a dose-intensity factor for platinum of 1.6, together with an increase in the TCD. However, no survival benefit was found, only increased toxicity. In four studies both the dose intensity per cycle and the TCD of platinum were doubled in combination with standard dose CTX 6 epidoxorubicin [18–22]. Only two of these four studies showed a benefit in OS [20–22]. However, Ngan et al. [20] included only 65 patients in a randomized study comparing the combination of CTX 600 mg/m2 with cisplatin 120 mg/m2 or 60 mg/m2. The 3-year survival was 60% with the high-dose regimen and 30% with the low-dose regimen at the cost of increased hematologic, renal and neurotoxicity. No long-term follow-up data of this study have been published. Kaye et al. [21, 22] compared CTX 750 mg/m2 combined with cisplatin 100 mg/m2 and 50 mg/m2. After a follow-up of 4.9 years, OS was increased from 27% to 32% with an overall relative death rate of 0.68 (P=0.043). It appeared, however, that the benefit of high-dose cisplatin was greatest during the first 2 years; the relative death rate after 2 years was 0.52 versus 1.30 after 4.9 years. Acute and late toxicity, which lasted for >4 years, were significantly higher in the high-dose group. The authors therefore recommended a lower cisplatin dose of 75 mg/m2 as providing the optimal balance between efficacy and toxicity.
viii34 | van der Burg et al.
increased dose intensity by weekly cisplatin administration An increase in the dose intensity can also be reached by reducing the interval between cycles (Table 2). In three studies weekly cisplatin was compared with standard 3-weekly cisplatin [23–25]. With the weekly regimen a two times higher dose intensity was reached with the same TCD. Bolis et al. [23] compared nine cycles of weekly cisplatin 50 mg/m2 with six cycles of 3-weekly CTX 750 mg/m2 plus cisplatin 75 mg/m2. Cocconi et al. [24] reported the results of six weekly versus six 3-weekly cycles of cisplatin (both at a dose of 100 mg/m2) followed by four cycles of doxorubicin and CTX in both arms. Fruscio et al. [25] compared nine weekly cycles of cisplatin 50 mg/m2 with six 3-weekly cycles of cisplatin 75 mg/m2. No significant differences in PFS or OS were observed between the dose-dense and control arms in the three studies, neither in the short term nor in the long term. The nonhematologic toxicity (especially ototoxicity), however, was substantial and significantly higher in the weekly arms.
dose-dense weekly platinum therapy in platinum-resistant patients In contrast to the negative outcome of dose-dense cisplatin in first-line therapy, weekly platinum combination therapy was shown to be highly effective in platinum-resistant disease (Table 3). Already in 1980, Piver et al. [26] found in 7 out of 10
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Gore et al., 1998 [14]
Experimental arm
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Annals of Oncology
Table 2. Dose intensity of first-line therapy in patients with advanced epithelial ovarian cancer reached by weekly cycles Study
No. of Standard arm patients
Bolis 607 et al., 1997 [23] Fruscio 285 et al., 2011 [25] Cocconi 101 et al., 1999 [24]
Van der Burg 263 et al., 2009 [37]
Planned DI factor
Increased Increased TCD survival
Increased toxicity
Cisplatin 50 mg/m2 q 1 weekly 2 · 9 cycles
No
No
No
Cisplatin 50 mg/m2 q 1 weekly 2 · 9 cycles Cisplatin 100 mg/m2 q 1 2 weekly · 6 cycles followed by CTX doxorubicin · 4 cycles
No
No
No
No
No
No
No Yes Yes
No
No
Yes No
Yes Yes; PFS 10.8 months, P = 0.0015; 3-year OS 7%, P = 0.03
Paclitaxel 90 mg/m2 + Paclitaxel 1.03, cisplatin 1.9, cisplatin 70 mg/m2 or carboplatin 1.3 carboplatin AUC 4 on days 1, 8, 15 + 29, 36, 43 followed by paclitaxel 175 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 6 q 3 weekly · 3–6 cycles Paclitaxel 80 mg/m2 Paclitaxel 1.3, Paclitaxel 180 mg/m2 carboplatin 1.0 +carboplatin AUC 6 q 3 on days 1, 8 + 15 + weekly · ‡6 cycles carboplatin AUC 6 on day 1 q 3 weekly · ‡6 cycles
DI factor, dose-intensity factor; TCD, total cumulative dose; q, repeated.
patients who had become resistant to conventionally dosed platinum a response when using six weekly cycles of cisplatin at a dose of 1 mg/kg followed by 60 mg/m2 every 3 weeks. Dose-dense weekly induction therapy with cisplatin 70 mg/m2 in combination with daily oral etoposide or weekly paclitaxel thus reached a 1.9-fold increased dose intensity, resulted in response rates of, respectively, 46% and 65%; these values are substantially higher than the £10% responses with conventional platinum chemotherapy [27–29]. In these studies, the median PFS was 5 and 8 months and the median OS was 10 and 11 months, respectively. When 3-weekly paclitaxel/carboplatin was shown to be equally effective but less toxic than 3-weekly paclitaxel/cisplatin in first-line treatment [6–8], weekly paclitaxel was combined with weekly carboplatin to reduce toxicity [30]. In this latter study, six weekly cycles with paclitaxel 90 mg/m2 and carboplatin AUC 4 induction therapy were followed by six cycles of 3-weekly paclitaxel 175 mg/m2 and carboplatin AUC 6 [30]. The overall response rate in the platinum-resistant patients was 58%, whereas 77% of patients had disease control (response + stable disease). The median PFS was 10 months (range 1–21) and the median OS was 12 months (range 1–69). In an attempt to further increase the efficacy, the weekly regimen was continued for 18 weeks in three studies. Cadron et al. [31] used the regimen of paclitaxel 90 mg/m2 and carboplatin AUC 4 on days 1 and 8 repeated (q) 21 days for six cycles; Havrilesky et al. [32] used paclitaxel 80 mg/m2 and carboplatin AUC 2 on days 1, 8 and 15 q 28 days until progression, SAE or 8 cycles after CR; and Sharma et al. [33] used paclitaxel 70 mg/m2 and carboplatin AUC 3 on days 1, 8 and 15 q 28 days for six cycles. In platinum-resistant
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patients they found response rates of 25%–38%, with the median PFS ranging from 3.2 to 8.7 months and the median OS from 6.8 to 11.4 months. Two studies investigated dose-dense weekly paclitaxel 90 mg/m2 combined with 4-weekly carboplatin AUC 5 [34, 35]. Hoekstra et al. [34] found in 5 platinum-resistant patients a response in 60%, while Lortholary et al. [35] found a response rate of 38% and a PFS of 4.9 months in 51 patients.
dose-dense weekly paclitaxel/ carboplatin in first-line therapy The positive results with weekly paclitaxel/platinum induction therapy in platinum-resistant ovarian cancer were the basis for a randomized first-line trial in advanced disease [36]. In this trial, patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV ovarian cancer were randomized between induction therapy with six cycles weekly paclitaxel 90 mg/m2 and cisplatin 70 mg/m2 or carboplatin AUC 4 on days 1, 8 and 15 and days 29, 36 and 43 versus three cycles of standard 3-weekly paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 6. In both arms treatment was followed by three to six 3-weekly cycles paclitaxel/platinum. Paclitaxel/ cisplatin was administered in the first 105 patients, after which cisplatin was replaced by carboplatin. In total, 267 eligible patients were randomized. No difference in response, PFS or OS was observed between the dose-dense weekly and the standard 3-weekly regimens. The median PFS was 19 months in the
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Katsumata 631 et al., 2009 [38]
Cisplatin 75 mg/m2 + CTX 750 mg/m2 q 3 weekly · 6 cycles Cisplatin 75 mg/m2 q 3 weekly · 6 cycles Cisplatin 100 mg/m2 q 3 weekly · 6 cycles followed by CTX doxorubicin · 4 cycles Paclitaxel 175 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 6 q 3 weekly · 6–9 cycles
Experimental arm
Study
Regimen
Platinum sensitivity
N (evaluable)
Van der Burg et al.,2005 [30]
P 90 mg/m2 + C AUC 4 on days 1, 8, 15 + 29, 35, 42 followed by PC q 3 weekly · 6 cycles P 90 mg/m2 + C AUC 4 on days 1 + 8 q 3 weekly · 6 cycles
All <6 months 6–12 months >12 months
62 23 19 20
All <6 months 6–12 months >12 months All <6 months >6 months
33 (29) 8 11 10 29 8 21
All Refractory <6 months >6 months All <6 months 6–12 months >12 months <6 months <6 months <6 months
21 5 7 9 20 5 5 10 57 51 57
Cadron et al., 2007 [31]
Havrilesky et al., 2003 [32]
Sharma et al., 2009 [33]
Hoekstra et al., 2009 [34]
Lortholary et al., 2011 [35]
CR (%)
PFS (months)
OS (months)
Toxicity Grade 3/4 % of patients Anemia Neutropenia Thrombocytopenia
Neurotoxicity
Hypersensitivity
64 64 89 79
10 14 47 16
11 10 12 11
20 14 29+ 32+
23
92
42
0
20
66 38 73 80 83 38 100
21 13 18 30 55 13 71
9 6.8 10.5 12.8 11.5 3.2 13.7
18 8 NR NR NR 11.4 NR
24
94
25
3
9
11
32
14
0
21
60 25 25 50 85 60 93
0
13.3 6.8 – 10.0 NR
5
30
0
14
14
75 40 87
7.9 8.9 5.5 7.8 –
0
35
0
0
25
35 38 39
14 5 10
3.7 4.8 5.4
19,9 15.2 19.9
6 19 27
13 54 42
447
32 20 30
2 16 7
N, number of patients; RR, response rate; CR, complete remission; PFS, progression-free survival; PD, progressive disease; NR, not reached; OS, overall survival; q, repeated; P, paclitaxel; C, carboplatin.
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P 80 mg/m2 + C AUC 2 on days 1, 8 + 15 q 4 weekly until PD/CR P 70 mg/m2 + C AUC 3 on days 1, 8 + 15 q 4 weekly · 6 cycles P 80 mg/m2 on days 1, 8 + 15 + C AUC 5 on day 1 q 4 weeks (a) P 80 mg/m2 on days 1, 8 + 15 (b) P 80 mg/m2 on days 1, 8 + 15 + C AUC 5 on day 1 (c) P 80 mg/m2 + topotecan 3 mg/m2 on days 1, 8 + 15 all regimens q 4 weekly
RR (%)
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Table 3. Dose-dense weekly paclitaxel + carboplatin in platinum-resistant progressive ovarian cancer
Annals of Oncology
discussion The intriguing results of the JGOG dose-dense study with weekly paclitaxel 80 mg/m2 on days 1, 8 and 15 combined with 3-weekly carboplatin AUC 6 are promising [37]. The median PFS for the dose-dense weekly paclitaxel/carboplatin regimen was 28 months, a significant improvement of 11 months compared with the standard 3-weekly paclitaxel 180 mg/m2 and carboplatin AUC 6. The 3-year OS rate was increased from 65% in the standard group to 72% in the dose-dense weekly group. These results, however, are in sharp contrast with the phase III results of other dose-intensity studies with cisplatin, carboplatin and weekly paclitaxel/platinum induction therapy (Table 1 and Table 2). Only two of the previously performed 12 dose-intense platinum studies, both with an increased cisplatin dose per cycle and an increased cumulative platinum dose, showed a survival benefit at the cost of important long-lasting toxicity, which hampered the further development of doseintense cisplatin [20–22]. No survival benefit was seen in the three studies with weekly cisplatin [23–25]. It is not clear why such a large difference exists between the JGOG study with weekly paclitaxel and 3-weekly carboplatin, and the study with weekly paclitaxel/platinum induction therapy. Despite the considerably higher hematologic toxicity, leading to frequent
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dose reductions, treatment delays and premature therapy discontinuation, and the relatively low response rate in the JGOG study, the PFS and OS are considerably longer in the dose-dense weekly paclitaxel plus 3-weekly carboplatin group of the JGOG study. Some investigators suggested that a more prolonged administration of weekly paclitaxel/carboplatin would be more efficacious than only using weekly induction therapy followed by the 3-weekly cycles. This weekly induction regimen followed by 3-weekly paclitaxel/carboplatin cycles, however, has proved to be very effective in platinum-resistant patients with a response rate of 58% and a median PFS of 10 months, and seems to be at least as effective as continuation of weekly paclitaxel/carboplatin for six cycles in platinum-resistant patients [31, 32] (Table 3). Also, there is no evidence that the regimen with weekly paclitaxel combined with 4-weekly carboplatin is more efficacious in platinum-resistant patients [34, 35]. In the phase II study with paclitaxel 80 mg/m2 on days 1, 8 and 15 and carboplatin AUC 5 on day 1 every 4 weeks for six cycles, the response rate was 38% and the PFS was only 5 months in contrast to the 10 months with weekly paclitaxel/carboplatin induction therapy. A difference between these phase II regimens and the JGOG study is a gap of 1 week in the paclitaxel administration per cycle. Although in the JGOG study no gap between the paclitaxel administrations was planned, treatment delays occurred frequently as a result of the hematologic toxicity. Not only in the JGOG dose-dense weekly group but also in the control arm of that study (the standard 3-weekly paclitaxel/ carboplatin group), severe myelosuppression was leading more to treatment delays, dose reductions and premature treatment discontinuations than observed when using standard 3-weekly paclitaxel/carboplatin therapy in the Caucasian patients. This suggests that Asian patients may be more susceptible to the toxicity of paclitaxel/carboplatin-containing treatment regimens and that their tumor cells seem to be more sensitive to paclitaxel/carboplatin. Phan et al. [38] reported a reduced drug clearance with increased toxicity and Soo at al. [39] found in a meta-analysis an increase in OS in Asian patients and a higher response rate in Asian non-small-cell lung cancer patients receiving carboplatin/paclitaxel. Genotypes and phenotypes are thought to represent important determinants of drug efficacy in ovarian cancer [40–44]. Especially, a silent polymorphism at codon 118 in the DNA repair gene excision repair cross complementation group 1 (ERCC1) was shown to be an independent predictor for better survival in patients with advanced EOC treated with intravenous paclitaxel/carboplatin-based chemotherapy [41]. Previously, the same authors showed in EOC patients with minimal residual disease treated with intraperitoneal paclitaxel/ cisplatin, a relationship between polymorphism C8092A in the 3# untranslated region of ERCC1 and survival, while codon 118, i.e. C118T, was not significant [42]. Moreover, preliminary evidence suggests that ethnic differences in the expression of allelic variants, e.g. the allele frequency of ERCC1 C and T is 70% versus 30% in Asians and 40% versus 60% in Caucasians, may result in altered pharmacokinetics and pharmacodynamics of anticancer drugs [43, 44].
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dose-dense weekly group and 18 months (P = 0.64) in the standard 3-weekly group, and the median OS was 44 and 43 months (P=0.86), respectively. The Japanese Gynecologic Oncology Group (JGOG trial no. 3016), on the contrary, showed a significant benefit in both PFS and OS in favor of the dose-dense regimen [37]. In this study, 631 eligible patients with FIGO stages II–IV disease were randomized between weekly dose-dense paclitaxel 80 mg/m2 on days 1, 8 and 15 combined with 3-weekly carboplatin AUC 6, versus standard 3-weekly paclitaxel 180 mg/m2 and carboplatin AUC 6. The median PFS and the 3-year OS were significantly longer in the dose-dense group: PFS was 28 months in the dose-dense group versus 17 months in the standard group (hazard ratio for progression, 0.71; 95% confidence interval, 0.58–0.88; P=0.0015); and the 3-year OS rate was 72% versus 65% (P=0.03), respectively. The response rate in the weekly dose-dense group was 56% compared with 53% in the 3-weekly standard group. More toxicity was observed in the weekly dose-dense group; 53% of patients in the dose-dense group but also 37% of the patients in the standard 3-weekly group stopped treatment prematurely. The main reason for discontinuing treatment was hematologic toxicity. Grade 3/4 neutropenia was observed in 92% and 80% of the patients and thrombocytopenia in 44% and 38%, respectively. In the randomized study with weekly paclitaxel/platinum induction therapy, on the contrary, 15% of patients in the dose-dense regimen and 16% in the standard 3weekly group stopped treatment prematurely [36]. Hematologic toxicity was considerably less compared with what was observed in the JGOG study; grade 3/4 neutropenia was observed in only 44% of the patients in the dose-dense group and in 32% in the standard group, whereas grade 3/4 thrombocytopenia was observed in only 12% and 5% in both groups, respectively.
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symposium article conclusion
disclosures The authors declare no conflict of interest.
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Only one (i.e. JGOG 3016) out of a total of 14 randomized dose-intensity studies in first-line therapy using weekly paclitaxel combined with 3-weekly carboplatin, and in fact the only study performed in Asian patients, showed a large difference in PFS and OS despite significant hematologic toxicity leading to dose reductions, treatment delays and premature discontinuation of treatment. Confirmatory studies with the JGOG regimen with well defined translational research are urgently needed. These studies should include Caucasian as well as Asian patients and should be stratified for tumor histotype as suggested in the recent The Cancer Genome Alas (TCGA) study [43]. Prospective pharmacogenetic analyses of the tumor i.e. single nucleotide polymorphisms in DNA repair pathways within tumor histotypes might aid in the clarification of the pharmacokinetic and pharmacodynamic impact of this schedule. It also gives more insight in the underlying molecular processes within ethnic subgroups of patients.
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39. Soo RA, Loh M, Mok TS et al. Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials. J Thorac Oncol 2011; 6: 1030–1038. 40. Smith S, Su D, Rigault de la Longrais IA et al. ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. J Clin Oncol 2007; 33: 5172–5179. 41. Krivak TC, Darcy KM, Tian C et al. Single nucleotide polymorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study. Gyn Oncol 2011; 122: 121–126. 42. Krivak TC, Darcy KM, Tian C et al. Relationship between ERCC1 polymorphisms, disease progression, and survival in the Gynecologic Oncology Group phase III trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian cancer. J Clin Oncol 2008; 20: 3598–3606. 43. O’Donnell PH, Gamazon E, Zhang W et al. Population differences in platinum toxicity as a means to identify novel genetic susceptibility variants. Pharmacogenetics Genomics 2010; 20: 327–337. 44. Bell D, Berchuch A, Birrer M et al. Integrated genomic analyses of ovarian carcinoma. Cancer Genome Atlas Research Network. Nature 2011; 474: 609–615doi:10.1038/nature10166.
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