Gynecologic Oncology 132 (2014) 1822

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Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Weekly carboplatin with paclitaxel compared to standard three-weekly treatment in advanced epithelial ovarian carcinoma a retrospective study
Tamar Safra a,, Sivan Shamai a, Julia Greenberg a, Anat Veizman a, Shulem Shpigel a, Dianna Matcejevsky a, Sharon Pelles a, Moshe Inbar a, Tally Levy b, Dan Grisaru c
a b c

Department of Oncology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Wolfson Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Division of Gynecologic Oncology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

H I G H L I G H T S Weekly and 3-weekly carboplatin/paclitaxel were compared in ovarian cancer patients. The weekly protocol improved progression-free survival with similar median overall survival. The weekly protocol showed decreased hair loss, neuropathy and hematologic toxicity.

a r t i c l e

i n f o

a b s t r a c t
Objective. To retrospectively compare primary treatment with weekly carboplatin/paclitaxel (PC-W) to the standard 3-weekly carboplatin/paclitaxel (PC-3W) in women with advanced epithelial ovarian cancer, tubal carcinoma and primary peritoneal carcinoma. Methods. Medical records were assessed for age, stage of disease, tumor histology and grade, BRCA mutation status, and platinum sensitivity. Patients were treated with either paclitaxel (175 mg/m2) and carboplatin (AUC 6) every three weeks (PC-3W; 133 patients), or with weekly paclitaxel (80 mg/m2) and weekly carboplatin (AUC 2) on days 1, 8, and 15 every 28 days (PC-W; 267 patients). Results. Patient baseline characteristics were similar in both groups. Median overall survival (OS) was similar for PC-W and PC-3W (64.5 months vs. 61.5 months), but PC-W had longer median progression-free survival [PFS: 27.4 months (95% CI, 22.731.4) vs. 19.5 months (95% CI, 15.622.2) for PC-3W, p = 0.0024] and a longer median platinum-free interval [PFI: 22.1 months (95% CI, 16.024.5) vs. 14.2 months (95% CI, 10.717.2) for PC-3W, p = 0.0075]. PC-W showed a signicantly higher response rate (86.4% vs. 77.9% for PC-3W, p = 0.0435). Multivariate analysis including for age at diagnosis, stage of disease, optimal debulking, histology, BRCA status, pretreatment CA-125 and PFI revealed that the PC-W women had lower risk of death (HR = 0.587, 95% CI, 0.4020.857, p = 0.0058), lower risk of disease progression (HR = 0.494, 95% CI, 0.3590.680, p b 0.0001), higher 2- and 3-year survival rates, and decreased grade II hair loss, neuropathy and thrombocytopenia compared with the PC-3W women. Conclusion. The PC-W protocol improved PFS and had a similar OS as PC-3W. 2013 Elsevier Inc. All rights reserved.

Article history: Received 13 February 2013 Accepted 11 June 2013 Available online 10 July 2013 Keywords: Ovarian cancer Weekly chemotherapy Survival Toxicity

Introduction Ovarian cancer is the fth leading cause of female cancer deaths in the United States [1]. The primary treatment of epithelial ovarian cancer
Corresponding author at: Department of Oncology, Tel Aviv Sourasky Medical Center Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. Fax: +972 3 6974789. E-mail address: safrat@bezeqint.net (T. Safra). 0090-8258/$ see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.06.013

(EOC) with cytoreductive surgery followed by six courses of combined chemotherapy with carboplatin [area under the curve (AUC) 57] and paclitaxel (175 mg/m2) administered every 3 weeks (PC-3W) [2] has a high initial response rate but the overall survival (OS) remains low because the recurrence rate is about 70% [35]. Attempts to improve survival outcomes by adding a third cytotoxic agent have not been successful thus far [6]. To date there are several acceptable treatment protocols for ovarian cancer primary treatment: (1) including intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel [7], and

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(2) bevacizumab plus paclitaxel/carboplatin followed by bevacizumab maintenance [8, 9]. Of all the regimens in current use, only intravenous paclitaxel plus intraperitoneal cisplatin was shown to be superior to the standard carboplatinpaclitaxel-based combination [10]. An additional treatment option is dose-dense therapy in which a higher cumulative dose is administered over a shorter period resulting in a reduced interval between doses, i.e., carboplatin is given every 3 weeks and paclitaxel is given weekly [11]. The rationale for such a treatment is the NortonSimon hypothesis assuming increasing dose density of chemotherapy increases its efcacy by minimizing the opportunity for regrowth of tumor cells between cycles [12]. Weekly paclitaxel-based combination chemotherapy (PC-W) has shown an increase in response rate (RR) [1317], PFS [1517] and OS [17] in treatment of recurrent ovarian cancer, especially in patients with platinumresistant disease. The efcacy of paclitaxel and reduced toxicity in PC-W might be attributed to its non-linear pharmacokinetics [18] and possible anti-angiogenic effects [1921]. It was also suggested that PC-W leads to immune activation while there is immunological exhaustion in the PC-3W protocol [22]. The level of activity of PC-W for relapsed disease has been evaluated in the rst-line setting. The Japanese Gynecological Oncology Group (JGOG) 3016 randomized phase III trial demonstrated a survival advantage for PC-W compared with PC-3W as primary treatment [11]. In that study, paclitaxel (80 mg/m2) was administered on days 1, 8, and 15 and carboplatin (AUC 6) was administered on day 1 every 21 days. Compared with the conventional regimen, the dose-dense regimen resulted in longer median PFS (28.0 months vs. 17.2 months, respectively) and higher OS at 3 years (72.1% vs. 65.1%, respectively). Early discontinuation due to toxicity was more common with this dose-dense regimen, and the patients were more likely to experience toxicity, especially neutropenia and anemia [11,23]. We previously reported a phase II study in 64 women diagnosed with stage Ic-IV EOC that combined treatments of weekly carboplatin (AUC 2) and weekly paclitaxel (80 mg/m2) given on days 1, 8, and 15 every 28 days [24]. With a median follow-up of 31.5 months (range 5.957.3 months), the estimated median OS was 52.0 months and the 2-year survival rate was 87.6%. A relatively low frequency of hematological toxicity, grade II hair loss and neuropathy was observed. Based on the promising results from that trial, we now present retrospective data comparing the outcome and toxicity of treatment with PC-W to those of the standard PC-3W protocol. Methods Medical records of patients diagnosed with and treated for EOC, fallopian tube carcinoma, or PPC from January 2003 to May 2012 in the Tel Aviv Sourasky Medical Center were reviewed. Institutional Review Boards and Cancer Center Research Review committee approvals, as well as waivers of informed consent to use de-identied information, were 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, co-morbidities, surgical management, rst-line chemotherapy, treatment toxicity, platinum sensitivity, rst platinum-free interval (PFI; PFI was calculated from end of primary treatment to either progression or death or to the last known follow-up), PFS, OS and status at the most recent follow-up. Treatment Chemotherapy was administered in six to eight cycles, either in a neoadjuvant setting in which 34 cycles were administered before cytoreductive surgery and 34 cycles were administered after the surgery, or as 6 cycles after cytoreductive surgery. The surgical method (i.e., primary surgery or surgery following neoadjuvant chemotherapy) was at the discretion of the treating physician. PC-W comprised of

weekly paclitaxel (80 mg/m2) and weekly carboplatin (AUC 2) given on days 1, 8, and 15 every 28 days. PC-3W comprised of paclitaxel (175 mg/m2) and carboplatin (AUC 6) given every three weeks was administered to all the other patients. The total time of the 6 cycle treatment was 18 weeks for the PC-3W and 24 weeks for the PC-W. Study endpoints The primary endpoint of the study was OS calculated from the initiation of treatment with carboplatin and paclitaxel to either death or to the last known follow-up. Secondary endpoints included RR, PFS, and safety. RR was dened as the composite of complete response (CR) and partial response (PR). PFS was calculated from initiation of treatment with carboplatin and paclitaxel to either progression or death or to the last known follow-up. Treatment modications Granulocyte colony-stimulating factor (G-CSF) and erythropoietin support were given at the discretion of the attending physician and prior to dose reduction. The chemotherapy dose was reduced by 25% for any grade III or IV toxicity (11.3% in the PC-W group and 8.6% in the PC-3W group, p = 0.44). The toxicity was graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). Paclitaxel was substituted with docetaxel (75 mg/m2 every 3 weeks) in the event of early-appearing grade II neurotoxicity. Assessment of safety and outcome Toxicities were evaluated according to NCI-CTC version 2. Toxicity evaluations and blood chemistry analyses were performed at the end of each cycle. Computerized tomography (CT) was performed every 3 cycles during chemotherapy treatment, every 3 months during the rst 2 years of follow-up, and every 6 months thereafter in patients receiving PC-W under the phase II study described above. All other patients underwent CT when clinically indicated at the discretion of the treating physician. The serum CA-125 level was evaluated monthly during treatment and every 3 months thereafter. Complete blood count (CBC) was performed before each treatment. Response was evaluated during and after completion of chemotherapy by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. CR was considered to be the disappearance of all known disease on CT scan and return of serum CA-125 levels to normal values (b 35 IU/ml) for at least 4 weeks. PR was considered to be a 30% decrease in the sum of the longest diameter of target lesions (evaluated by CT scan) in measurable disease or a N 50% decrease in serum levels of CA-125 (conrmed with repeat serum CA-125 level assessments in no less than 4 weeks). A conrmed increase in the serum CA-125 level to more than twice the upper limit of normal values was used to diagnose disease for patients with elevated serum CA-125 levels and no morphologic evidence of disease. Statistical methods All data were summarized and displayed as median and range for all continuous variables, and as number and percentage in each group for categorical variables. Survival functions were demonstrated using the KaplanMeier method. In addition, univariate comparisons of continuous variables between groups was performed using the independent Student's t-test, and Fischer's exact test or chi-square test were used for categorical variables. Survival analysis using the Cox proportional hazards model was performed to compare the risk of death and the risk of recurrence between the two treatment regimens, including for age, stage of disease (grouped into two categories, I + II and III + IV), level of debulking, histology (mucinous/clear cell/poorly differentiated tumor vs. serous

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T. Safra et al. / Gynecologic Oncology 132 (2014) 1822

papillary/endometrioid/adenocarcinoma), BRCA status (carriers vs. noncarriers, and non-carriers vs. untested patients) and pre-treatment CA-125 (b 500 U/ml and 500 U/ml). The model for OS was also adjusted for PFI b 6 months. Results are presented as the hazard ratio (HR) and the 95% condence interval (CI). A receiver operator characteristic curve was applied to the data to locate the cutoff point of CA-125 pretreatment that may predict death with optimal sensitivity and specicity. The level of signicance used for all of the above analyses was two-tailed, and a p value of b 0.05 was considered signicant. The SAS for Windows version 9.2 was used to perform all statistical analyses (SAS Institute Inc., Cary, NC, USA). Results A total of 466 consecutive medical records were examined. Those whose rst-line treatment consisted of other platinum-based combinations, such as carboplatin alone or platinum cytoxan were excluded. The nal study group comprised of 400 women who were treated with carboplatin plus paclitaxel for EOC, tubal carcinoma or PPC. Onehundred and thirty-three patients (33.25%) received PC-W, and 267 (66.75%) received PC-3W. All patients were evaluated for drug efcacy and toxicity. The baseline characteristics of patients treated with PC-W and PC-3W were similar (Table 1). Their median age was 60.2 years (range: 2286). Most of the patients (n = 336, 84.6%) had stage III and IV diseases. One-half of them (n = 198, 50.0%) had serous papillary disease, and 158 (39.9%) had endometrioid carcinoma. The remaining 44 women had mucinous, clear cell or undifferentiated histology. Over one-half of the patient population (225/400, 56.4%) was tested for BRCA carrier status: 24% (54/225) were BRCA1 mutation carriers and 11.6% (26/225) were BRCA2 mutation carriers. Thus, almost twothirds of those tested for BRCA status, were non-carriers (145/225, 64.4%). There was no signicant difference in the proportion of patients from both groups who received neoadjuvant treatment (60/132, 45.5% of patients treated with PC-W and 102/265, 38.5% of the patients treated with PC-3W; p = 0.1835). There was, however, a signicant difference between the two treatment regimens for optimal debulking (69/121, 57.0% vs. 173/255, 67.8% for PC-W and PC-3W, respectively, p = 0.0407). Outcome The median follow-up was 65.5 months (95% CI, 52.474.2). KaplanMeir analysis showed that the difference in OS between the
Table 1 Patient characteristics. Characteristics No. of patients (%) Total Age, mean (range), years Disease stage at diagnosis (WHO criteria) III IIIIV Histologic type Serous papillary carcinoma Endometrioid carcinoma/adenocarcinoma Mucinous carcinoma/clear cell/poorly differentiated Undifferentiated Platinum sensitivity Sensitive Resistant BRCA status BRCA I BRCA II Negative Not tested Pretreatment CA-125 (U/ml) Neoadjuvant treatment Optimal debulking 60.2 (2286) 54 (13.6) 336 (84.6) 198 (50.0) 158 (39.9) 33 (8.3) 7 (1.8) 204 (72.6) 76 (27.1) 54 26 145 172 (13.6) (6.6) (36.5) (43.3)

two groups was not statistically signicant, although the median OS of 64.5 months (95% CI, 52.486.4) in PC-W was longer than that in PC-3W (61.5 months, 95% CI, 47.172.6) (Fig. 1 and Table 2). The survival rate after 2 and 3 years was higher in patients treated with PC-W. Specically, the 2-year survival rate was 87% for PC-W and 81.8% for PC-3W, and the 3-year survival rate was 79.9% for PC-W and 69.8% for PC-3W. A signicantly higher RR was observed for PC-W compared with that for PC-3W (86.4% vs. 77.9%, respectively, p = 0.0435). The median PFS of 27.4 months (95% CI, 22.731.4) was signicantly longer in patients treated with PC-W compared with 19.5 months (95% CI, 15.622.2) for those treated with PC-3W (p = 0.0024, Table 2 and Fig. 2). The proportion of patients who were platinum sensitive was similar in both treatment groups (71.3% and 73.3% respectively; p = 0.397; Table 1). PFI was signicantly longer in patients treated with PC-W (22.1 months, 95% CI, 16.024.5) compared with patients treated with PC-3W (14.2 months, 95% CI, 10.717.2; p = 0.0075, Table 2). Survival analysis using the Cox proportional hazards model was performed to compare the risk of death and the risk of recurrence both from end of primary therapy and from start of primary chemotherapy between the two treatment regimens, adjusting for age, stage of disease (grouped into 2 categories, 1 + 2 and 3 + 4), debulking, histology, BRCA status and pre-treatment CA-125 (grouped into 3 categories (b 500, 500800, N 800)). The model for overall survival included also PFS grouped into 2 categories: below and above 6 months. PC-W patients were at a signicantly lower risk for death when compared with the PC-3W patients (HR, 0.680, 95% CI, 0.4850.953, p = 0.0252). BRCA, incomplete debulking, stage III + IV and PFI b 6 are risk factors for survival (HR, 1.490, 95% CI, 1.0612.092, p = 0.0212; HR, 2.311, 95% CI, 1.6723.194), p b 0.0001; HR, 2.329, 95% CI, (1.2904.205, p = 0.0051 HR, 0.137, 95% CI, 0.0950.197, p b 0.0001, respectively). BRCA carriers are at a signicantly lower risk for death when compared with non-carriers (HR, 0.556, 95% CI, 0.3560.869, p = 0.0252). PC-W patients had lower risk for recurrence compared with PC-3W patients (HR, 0.580, 95% CI, 0.4380.770, p = 0.0002). Incomplete debulking and stage are risk factors for PFI ((HR, 2.099, 95% CI, 1.614 2.730, p b 0.0001), (HR, 2.874, %95 CI, 1.8174.565, p b 0.0001), respectively). PC-W patients had lower risk for recurrence compared with PC-3W patients (HR, 0.536, 95% CI, 0.4030.712, p b 0.0001). Incomplete debulking and stage are risk factors for PFS ((HR, 2.154,

Weekly 65.0 (3486) 13 (9.9) 116 (87.9) 70 (53.0) 46 (34.9) 14 (10.6) 2 (1.5) 72 (71.3) 28 (27.7) 20 (15.2) 6 (4.6) 51 (38.6) 55 (41.7) 60 (45.5) 69 (57.0)

3-Weekly 59.0 (2286) 41 (15.5) 220 (83.0) 128 112 19 5 (48.5) (42.4) (7.2) (1.9)

p-value (2)

0.0901

0.4028

132 (73.3) 48 (26.7) 34 20 94 117 (12.8) (7.6) (35.5) (44.2)

0.3973

0.5874 0.1835 0.0407

162 (40.8) 242 (64.4)

102 (38.5) 173 (67.8)

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Survival Distribution Function

Survival Distribution Function

0 25 50 75 100 125 150 175 200

1.00

1.00

0.75

0.75

0.50

0.50

0.25

0.25

0.00

0.00 0 20 40 60 80 100 120 140

Overall Survival (months)

STRATA:
Weekly 3-Weekly

Progression-free Survival (months)

STRATA:
Weekly 3-Weekly

Fig. 1. KaplanMeier curve for overall survival.

Fig. 2. KaplanMeier curve for progression-free survival in patients.

95% CI, 1.6552.803, p b 0.0001), (HR, 2,892, 95% CI, 1.8294.573, p b 0.0001) respectively). Safety assessment Safety was assessed in all 400 patients (Table 3). A signicantly lower proportion of patients treated with PC-W had grade II hair loss compared with those treated with PC-3W (23.5% vs. 98.1%, respectively, p b 0.0001). A higher proportion of patients treated with PC-W reported grade III + IV neutropenia compared with those treated with PC-3W (14.4% vs. 6.9%, respectively). Thrombocytopenia was reported in a lower proportion of patients treated with PC-W compared with those treated with PC-3W (grade III + IV: none vs. 2.3%, respectively). Anemia was reported in a higher proportion in patients treated with PC-W compared with those treated with PC-3W (grade III + IV: 6.8% vs. 5.3%). There was a signicant difference in the occurrence of neuropathy between treatments: both grade III + IV and grade I + II neuropathy occurred in a lower proportion of PC-W recipients compared with PC-3W recipients (grade III + IV: 0.8% vs. 4.5%; grade I + II: 18.2% vs. 29.8%, p = 0.0208). The proportion of nausea, vomiting, diarrhea and neutropenic fever was similar in both treatment groups (Table 3). Treatment support (e.g., G-CSF and erythropoietin) was administered similarly under both treatment regimens (data not shown). It is noteworthy that there were 71 episodes of dose reduction in the PC-3W group compared to only 23 in the PC-W group. Discussion The promising ndings from our previously reported phase-II study of weekly carboplatin and paclitaxel [24] and the notable results of the JGOG dose-dense regimen [11] prompted us to retrospectively investigate the patient population treated for EOC, fallopian tube carcinoma, or PPC at our medical center and compare the outcome of rst-line treatment with PC-W with that of the standard PC-3W protocol. PC-W provides the same total cumulative dose as that of the dosedense protocol (240 mg/m2 per cycle) and a similar dose density (mg/m2/week) as that of PC-3W. The results of the current study showed that rst-line therapy of advanced EOC patients with weekly paclitaxel/carboplatin with a one-week interval between cycles is reasonably tolerated. OS for PC-W was similar to that of PC-3W, and

Table 2 KaplanMeier Analysis. Weekly median (95% CI) PFS, months OS, months 27.4 (22.731.4) 64.5 (52.486.4) 3-Weekly median (95% CI) 19.5 (15.622.2) 61.5 (47.172.6) p-value (log rank) 0.0024 0.2243

PFS, progression-free survival; OS, overall survival.

PFS was improved. Women assigned to PC-W had a 50.6% lower risk of disease progression and a 41.3% lower risk of death than patients receiving PC-3W. In addition, patients treated with PC-W had a 46.9% higher probability for higher 2- and 3-year survival rates. BRCA carriers were at a 38.8% lower risk of death compared to non-carriers. Although it was claimed that toxicity may be higher under PC-W treatment [25], the current ndings showed a lower incidence of grade III + IV thrombocytopenia, weakness and neuropathy. Furthermore, grade II hair loss was signicantly less in patients treated with PC-W, while the incidence of diarrhea, vomiting and neutropenic fever as well as the need for treatment support was similar for both protocols. The JGOG 3016 study demonstrated a survival advantage for dosedense PC-W compared with PC-3W as primary treatment [11], with a longer median PFS (28.0 months vs.17.2 months) and a higher OS at 3 years (72.1% vs. 65.1%), but with signicantly more toxicity. Our current results also demonstrated improved 2- and 3-year survival (87% and 79.9%, respectively) in patients treated with PC-W compared with those treated with PC-3W. Other similar studies have also reported improved activity and tolerability of PC-W, albeit at different paclitaxel doses. Sehouli et al. [26] reported 129 patients enrolled into a phase-II study of rst-line weekly administration of 100 mg/m2 paclitaxel and weekly carboplatin AUC 2, and showed substantial activity and tolerability of this regimen. However, the median PFS of 22 months and the median OS of 45 months did not exceed rates expected with standard treatment, and there was a high incidence of grade III/IV anemia. Pignata et al. [27] suggested that rst-line treatment with paclitaxel 60 mg/m2 on days 1, 8 and 15 every 4 weeks and weekly carboplatin at a dose of AUC 2 may be suitable for the elderly ( 70 years) patient population. The 2011 National Comprehensive Cancer Network (NCCN) ovarian cancer guidelines panel mention the use of dose-dense paclitaxel as rst-line treatment of stage II, III, or IV EOC, while suggesting that patients should be made aware of the increased toxicity of such treatment [28]. Awareness of this increased toxicity often leads to reluctance of physicians and patients to use this protocol, whereupon the PC-3W regimen continues to be the standard of care in many institutes. Our results propose an alternative regimen that is based on similar biological assumptions of dose density, while showing improved PFS with impressive 2- and 3-year survival rates. PC-W is currently being evaluated in two large phase III randomized trials the MITO 7 trial and the ICON-8 study. There are several limitations in this study. First, it is a retrospective chart review. Second, the follow-up schedule for the two treatment regimens was not identical because the PC-W-treated patients were followed more closely and were evaluated for toxicity weekly. Therefore, there is a possible under-estimation of bone marrow toxicity in the PC-3W group since additional/mid-cycle bone marrow toxicity in the PC-3W group may not have been reported. Third, a proper comparison to dose-dense or PC-3W regimens with a prospective randomized

22 Table 3 Toxicity prole. Toxicity

T. Safra et al. / Gynecologic Oncology 132 (2014) 1822

Number of patients, n (%) Weekly 3-Weekly III + IV 19 (14.4) 9 (6.8) 0 (0.0) 8 (6.1) 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.8) 31 (23.5) I + II 242 (93.1) 131 (49.4) 85 (32.1) 77 (29.6) 79 (29.8) 58 (22.1) 40 (15.3) 20 (7.7) 3 (1.1) III + IV 18 (6.9) 14 (5.3) 6 (2.3) 25 (9.6) 12 (4.5) 4 (1.5) 3 (0.8) 2 (0.8) 260 (98.1)

p value (2)

Grade Hematologic Neutropenia Anemia Thrombocytopenia Non-hematologic Weakness Neuropathy Nausea Vomiting Diarrhea Hair loss

I + II 113 (85.6) 82 (62.1) 29 (22.0) 70 (53.4) 24 (18.2) 41 (31.3) 26 (19.8) 16 (12.3) 100 (75.8)

0.0168 0.0248 0.0178 b 0.0001 0.0208 0.0603 0.1505 0.3837 b 0.0001

phase II study was not done here and possible (although not suspected) reduced efcacy was not ruled out. Our experience has shown that when all options are presented to the patients, they often choose the PC-W regimen because of its reduced toxicity, in the expectation that it may allow a better quality of life. In conclusion, the current study shows that PC-W is similar to PC-3W in terms of OS and toxicity.
Conict of interest statement The authors declare no potential conict of interest.

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Acknowledgment The authors thank Esther Eshkol for the editorial assistance. References

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