Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

GYNAECOLOGY

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative Sarah Glaze, MD, FRCSC,1 Lisa Teitelbaum, MD,2 Pamela Chu, MD, FRCSC,1 Prafull Ghatage, MBBS, FRCSC,1 Jill Nation, MD, FRCSC,1 Gregg Nelson, MD, PhD, FRCSC1 1

Department of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary AB

2

Department of Obstetrics and Gynecology, University of Calgary, Calgary AB

Abstract

Résumé

Objective: Epithelial ovarian cancer is the leading cause of death from gynaecologic cancers in the Western world. If possible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy, usually with a platinum/taxane combination. Increased survival has been recently reported in women who were given adjuvant chemotherapy weekly rather than at three-week intervals, which has been the standard. At our centre, we have been treating patients with advanced ovarian cancer with a dose-dense protocol since March 2010. Treatment is given in an outpatient setting on days 1, 8, and 15 of a 21-day cycle for six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80mg/m2 are given on day 1, followed by paclitaxel 80mg/m2 on days 8 and 15. Our objective was to determine whether this protocol is a feasible alternative treatment in our population and whether or not the toxicity profile is acceptable.

Objectif : Le cancer épithélial de l’ovaire est la principale cause des décès attribuables à des cancers gynécologiques en Occident. Dans la mesure du possible, la mise en œuvre d’une chirurgie de réduction tumorale initiale constitue le traitement à privilégier, le tout étant suivi de l’administration d’une chimiothérapie adjuvante (habituellement au moyen d’une combinaison platine / taxane). Un taux accru de survie a récemment été signalé chez des femmes à qui l’on a administré une chimiothérapie adjuvante selon un schéma hebdomadaire, plutôt qu’à intervalles de trois semaines (lequel schéma constituait la norme). Au sein de notre centre, nous traitons les patientes atteintes d’un cancer avancé de l’ovaire au moyen d’un protocole « dose-dense » (dans le cadre duquel les agents sont administrés à intervalles plus rapprochés) depuis mars 2010. Le traitement est administré en clinique externe aux jours 1, 8 et 15 d’un cycle de 21 jours, pendant six cycles. Du carboplatine (pour une SSC de 5 mg/ml/min) et du paclitaxel (80 mg/m2) sont administrés au jour 1, et du paclitaxel (80 mg/m2) est ensuite administré aux jours 8 et 15. Notre objectif était de déterminer si ce protocole constitue un traitement de rechange faisable pour notre population et si son profil de toxicité est acceptable.

Methods: We performed a chart review of 46 patients undergoing treatment with dose-dense chemotherapy for advanced ovarian cancer. Demographic information, patient characteristics, adverse events, and treatment endpoints were recorded. Results: Sixty-one percent of women completed the six-cycle protocol as planned with minimal interruption, which is comparable to the only previously reported trial using this regimen. The most common side effects of treatment were fatigue, neuropathy, and neutropenia. Supplementation with regular magnesium and granulocyte colony-stimulating factor reduced delays. Conclusion: Dose-dense paclitaxel with carboplatin chemotherapy for the treatment of advanced ovarian cancer shows promise in terms of progression-free and overall survival. We have shown this protocol to be practical and feasible in our population.

J Obstet Gynaecol Can 2013;35(1):61–67 Key Words: Ovarian neoplasms, chemotherapy protocols Competing interests: None declared. Received on July 25, 2012 Accepted on August 20, 2012

Méthodes : Nous avons mené une analyse des dossiers de 46 patientes recevant un traitement au moyen d’une chimiothérapie « dose-dense » en raison de la présence d’un cancer avancé de l’ovaire. Les données démographiques, les caractéristiques de la patiente, les événements indésirables et les critères d’évaluation du traitement ont été consignés. Résultats : Soixante et un pour cent des femmes ont complété le protocole de six cycles tel que prévu sans grandes interruptions, ce qui est comparable aux résultats obtenus dans le cadre du seul essai auparavant signalé ayant utilisé un tel schéma. Les effets indésirables les plus courants du traitement ont été la fatigue, la neuropathie et la neutropénie. La supplémentation au moyen de magnésium régulier et de facteur de croissance hématopoïétique G-CSF a permis de réduire les délais. Conclusion : La mise en œuvre d’une chimiothérapie « dosedense » faisant appel au paclitaxel et au carboplatine pour le traitement du cancer avancé de l’ovaire s’avère prometteuse pour ce qui est du taux global de survie sans progression. Nous avons démontré que ce protocole était pratique et faisable pour notre population.

JANUARY JOGC JANVIER 2013 l 61

Gynaecology

INTRODUCTION

O

varian cancer is the leading cause of death from gynaecologic cancers in the Western world.1 It is normally initially chemosensitive, and most ovarian cancers demonstrate a 75% to 80% response rate.2 However, most women have recurrence of disease within 12 to 18 months, after which they are no longer considered curable. Cytoreduction is the cornerstone of treatment for ovarian cancer. The volume of residual disease after surgery correlates inversely with survival.3 The definition of optimal surgical debulking is becoming more stringent and has recently been described as the achievement of microscopic residual disease.4 Whether this is achieved by neoadjuvant chemotherapy before surgery or aggressive initial debulking, it is intuitive that the smaller the residual tumour, the more easily it can be treated with chemotherapy. Larger tumours have poorer vascular perfusion, a greater chance of causing sub-lethal damage, and the potential for emergence of drug resistance. However, even with rigorous preoperative patient selection and aggressive surgery, some patients are left with macroscopic residual tumour. Adjuvant chemotherapy for the treatment of this malignancy is as important as surgical cytoreduction for disease control. The evolution of chemotherapy for the treatment of ovarian cancer has been complex. The armamentarium is large; many available chemotherapeutic agents have some measurable therapeutic effect and have been used to treat ovarian cancer.5 The platinum era of the 1970s marked the first significant increase in survival with adjuvant chemotherapy. Since the 1990s the combination of platinum with paclitaxel has been considered first-line treatment. Despite numerous modifications of the dose, timing, and duration of these drugs, and the addition of other agents, there was a plateau in survival until the introduction of intraperitoneal chemotherapy. Two recent large meta-analyses encompassing multiple randomized trials demonstrated better progression-free and overall survival in women undergoing treatment with combined intravenous and intraperitoneal chemotherapy than in those receiving intravenous treatment alone.6,7 Deborah Armstrong led a landmark Gynecologic Oncology Group study published in 20068 that solidified intraperitoneal delivery of chemotherapy as an important treatment strategy, and many centres began offering protocols ABBREVIATIONS ANC

absolute neutrophil count

AUC

area under the curve

TBCC

Tom Baker Cancer Centre

62 l JANUARY JOGC JANVIER 2013

using the regimen described. However, there were some difficulties innate to this form of drug delivery, and questions lingered about what was responsible for the improved clinical outcomes: it was uncertain whether it was truly the mode of delivery of the chemotherapy, or the fact that the patients received two doses of paclitaxel one week apart. Other tumour groups have found some success with doseintense or dose-dense therapies. Weekly paclitaxel has been used in the treatment of breast cancer and small cell lung cancer, with response rates in the order of 50% to 80%.9 These impressive results encouraged investigation of dose-intense chemotherapy as a treatment strategy in ovarian cancer. A number of regimens have been reported, including weekly cisplatin and daily oral etoposide, weekly paclitaxel, and weekly cisplatin with paclitaxel.10 These regimens were reasonably well tolerated with seemingly good response rates. Further studies, modifying the gold standard carboplatin with additional weekly paclitaxel regimens, were undertaken and eventually led to promising phase 2 trials,11 but a large-scale randomized controlled trial to confirm these promising results was missing. This changed in 2009, when the Japanese Gynecologic Oncology Group conducted a phase 3 randomized controlled trial to examine the benefit of a dose-dense regimen for treatment of ovarian cancer. Katsumata et al. reported increased median progression-free and three-year survival in women treated with a dose-dense protocol,12 with continuation of this trend at 6.4 years of median follow-up.13 Since March 2010, the gynecologic oncology group at the Tom Baker Cancer Centre in Calgary, Alberta has been treating patients with advanced ovarian cancer with a dosedense protocol similar to that described by Katsumata et al. Other centres in North America have not yet reported on the use of a similar regimen. The objective of this study was to determine whether this protocol is a feasible treatment alternative and whether or not the toxicity profile is acceptable in our population. METHODS

The TBCC is a tertiary level cancer facility located in Calgary, Alberta that provides comprehensive cancer care for patients from southern Alberta, with referrals from both western Saskatchewan and eastern British Columbia. An electronic medical chart is used to record all patient information at TBCC from initial consultation to post-

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

Table 1. Protocol for dose-dense paclitaxel and carboplatin (Calgary modification) Prior to initiation of treatment

Vitamin B6 100 mg daily by mouth (for duration of treatment) Vitamin E 400 IU daily by mouth (for duration of treatment) Ciprofloxacin 250 mg daily by mouth (for duration of treatment)

Day 1

Carboplatin for an AUC of 5 mg/mL/min IV Paclitaxel 80 mg/m2 IV Ranitidine 50 mg IV Diphenhydramine 50 mg IV Dexamethasone 12 mg IV Lorazepam 1 mg sublingually Granisetron 1 mg IV MgS04 2000 mg IV piggy-back

Day 8

Paclitaxel 80 mg/m2 IV Ranitidine 50 mg IV Diphenhydramine 50 mg IV Dexamethasone 12 mg IV Lorazepam 1 mg sublingually Granisetron 1 mg IV MgS04 2000 mg IV piggyback

Day 15

Paclitaxel 80 mg/m2 IV Ranitidine 50 mg IV Diphenhydramine 50 mg IV Dexamethasone 12 mg IV Lorazepam 1 mg sublingually Granisetron 1 mg IV MgS04 2 g IV piggy-back

Cycles 2 to 6

Filgrastrim 300 μg subcutaneously on days 4, 5, 6, 9, 10, 16, 17, 18

treatment follow-up. Women with advanced ovarian, fallopian tube, and primary peritoneal cancer who were offered adjuvant chemotherapy were offered this in a dose-dense protocol. All patients who received dose-dense paclitaxel and carboplatin chemotherapy from March 2010 (initiation of program) to September 2011 were identified. From the medical charts of these 46 women, we extracted demographic information, details of diagnosis and treatment, and preliminary outcome data. Toxicity of chemotherapy was recorded from clinic notes and nurse memoranda between visits. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 3.0.14 After gaining experience with our first patients, a number of adjustments were made to the original protocol of Katsumata et al. This “Calgary modification” is described in Table 1. Whereas patients in the trial of Katsumata et al. did not receive prophylactic granulocyte-colony stimulating factor (G-CSF),12 we found that routinely administering filgrastim (a G-CSF analogue), beginning in cycle 2,

reduced treatment delays due to neutropenia. Because we noted significant hypomagnesemia in the majority of patients, we began routinely giving intravenous magnesium sulphate at every treatment. Chemotherapy was given in an outpatient setting on days 1, 8, and 15 of a 21-day cycle for an anticipated six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80 mg/m2 were given on day 1, followed by paclitaxel 80 mg/m2 on days 8 and 15. The dose of carboplatin was calculated using the Calvert formula.15 Carboplatin used with other chemotherapeutic agents can be particularly myelotoxic.5 At our centre, we prefer to use carboplatin at a dose aimed at AUC of 5 mg/mL/min if used in combination. Lower dose carboplatin is established as mounting a response against ovarian cancer equivalent to higher doses.16 Standard pre-medications were given to prevent hypersensitivity reactions. Common anti-emetics, including aprepitant, were routinely available to our patients. Before JANUARY JOGC JANVIER 2013 l 63

Gynaecology

each cycle, complete blood count, serum electrolytes, serum magnesium, serum creatinine, and liver function tests were reviewed. At the TBCC, patients are assessed in the clinic by a gynaecologic oncologist or resident/fellow prior to every other cycle of chemotherapy. An absolute neutrophil count ≥ 1.5 × 109 cells/L and a platelet count ≥ 100 × 109/L are required to proceed with treatment.

of adjuvant treatment as planned. Seven women (15%) stopped chemotherapy altogether, after an average of 4.1 cycles. One of these women died from disease progression during treatment. Other reasons for discontinuing treatment included neuropathy, neutropenia, patient preference, and anemia (Table 5).

Interval debulking surgery was undertaken after three cycles of neoadjuvant three-weekly carboplatin for an AUC of 5 mg/mL/min and paclitaxel 175 mg/m2. Second-look surgery was rarely performed after six cycles of chemotherapy, and only after significant residual disease was noted at the time of primary surgery; malignancy was an unexpected finding. Adjuvant chemotherapy was initiated at four to six weeks after surgery. All patients who discontinued the protocol prematurely were switched to three-weekly carboplatin for an AUC of 5 mg/mL/min and paclitaxel 175mg/m2 or single-agent carboplatin for an AUC of 6 mg/mL/min IV to complete a total of six treatment cycles.

DISCUSSION

Approval from the Alberta Cancer Research Ethics Committee was obtained prior to initiating the study. RESULTS

Forty-six patients underwent treatment with carboplatin and dose-dense paclitaxel at the TBCC between March 2010 and September 2011. Patient characteristics are reported in Table 2. The mean age of women in our cohort was 58 years. Most patients were high-functioning, with advanced disease. The most common histologic type was poorly differentiated serous carcinoma. The most frequently reported disease site was the ovary. Toxicity is described in Table 3. Fatigue, neuropathy, and neutropenia were the most commonly reported grade 3 or 4 events. Other adverse events included anemia, myalgia, and electrolyte abnormality. Hypomagnesemia was common in the first patients treated with this regimen, necessitating the addition of weekly magnesium administration to our protocol. After noting profound neutropenia in our first patients, we also added prophylactic filgrastim, as described in Table 1, starting in cycle 2. With this, we noted only 35% of patients experienced grade 3 or 4 neutropenia. No patients in our study suffered febrile neutropenia. The majority of women (61%) completed the treatment as planned for a total of six cycles (Table 4). Eleven women (24%) were switched to another regimen, most commonly to three-weekly carboplatin and paclitaxel. All of these women went on to complete a total of six cycles 64 l JANUARY JOGC JANVIER 2013

Ovarian cancer is among the most deadly malignancies in North American women. If feasible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy. Drug regimens have evolved over the years, but platinum and taxane combinations have long been considered standard. Second- and further-line regimens are not as well established.5 Recent developments in ovarian cancer treatment have focused on drug delivery through intraperitoneal ports. Armstrong et al. conducted a landmark study in 2006 comparing standard intravenous chemotherapy with an intraperitoneal regimen.8 Women who had minimal residual disease after surgery were randomized to receive standard intravenous paclitaxel and cisplatin every three weeks or intravenous cisplatin in combination with intraperitoneal cisplatin and paclitaxel given in the first and second weeks of a three week cycle. Each arm received treatment for six cycles if it was tolerated. The study demonstrated improvement in both progressionfree and overall survival in the intraperitoneal chemotherapy cohort. However, this treatment is not necessarily applicable to all cases; the women included in the study all had optimally cytoreduced disease at their initial surgery, a stringent requirement that is not always achievable surgically. In addition, the port system resulted in catheter-related complications that often necessitated early discontinuation.8 In 2009, Katsumata et al. published the influential Japanese Gynecologic Oncology Group dose-dense chemotherapy study.12 More than 600 women received six cycles of conventional chemotherapy (paclitaxel 180 mg/m2 plus carboplatin for an AUC of 6 mg/mL/min given on day 1 of a 21-day cycle) or a dose-dense paclitaxel (80 mg/m2 given on days 1, 8, and 15 plus carboplatin given on day 21). Median progression-free survival was longer in the dose-dense treatment group (28.0 months vs. 17.2 months), as was three-year survival (72.1% vs. 65.1%).12 Although withdrawal from the trial in the dose-dense protocol was higher because of toxicity, the only significant adverse effect greater in this cohort was grade 3 and 4 anemia. This study has been noteworthy, not only for its encouraging results,

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

Table 2. Patient characteristics (n = 46) Age in years, mean (range)

58 (33 to 79) n (%)

Table 3. Frequency of grade 3 or 4 events (common terminology criteria for adverse events) Event

n (%)

Fatigue

19 (41)

23 (50)

Neuropathy

17 (37)

ECOG 1

18 (39)

Neutropenia

16 (35)

ECOG 2

2 (4)

Anemia

9 (20)

Not recorded

3 (7)

Myalgia

3 (7)

Baseline ECOG performance status ECOG 0

Electrolyte abnormality

3 (7)

2 (4)

Thrombocytopenia

2 (4)

Stage II

9 (20)

Diarrhea

1 (2)

Stage III

29 (63)

Arthralgia

1 (2)

Stage IV

6 (13)

Other (pulmonary embolus, deep vein thrombosis, agitation, hives)

7 (15)

FIGO stage Stage I

Disease site Ovary

41 (89)

Fallopian tube

4 (9)

Primary peritoneal

1 (2)

Surgery Primary debulking

35 (76)

Interval debulking

9 (20)

Second look

2 (4)

Residual disease (primary surgery), n = 35 Residual disease > 1 cm

4 (11)

Residual disease ≤ 1 cm

11 (31)

Microscopic residual

16 (46)

Not reported

4 (11)

Residual disease (interval debulking), n = 11 Residual disease > 1 cm

2 (18)

Residual disease ≤ 1 cm

4 (36)

Microscopic residual

5 (45)

Table 4. Treatment endpoint Completed treatment, n (%)

28 (61)

Switched to another regimen, n (%)

11(24)

Carboplatin/paclitaxel every 3 weeks, n (%)

10 (91)

Carboplatin/doxorubicin every 3 weeks, n (%)

1 (9)

Drop-out, n (%)

7 (15)

Average number of completed cycles Treatment delay, n (%) (may have had any treatment endpoint) Average length of delay in days

4.1 28 (61) 7.9

Histology Serous

34 (74)

Endometrioid

6 (13)

Clear cell

4 (9)

Mucinous

2 (4)

Histological grade Well differentiated

5 (11)

Moderately differentiated

8 (17)

Poorly differentiated

30 (65)

Unknown ECOG: Eastern Cooperative Oncology Group

3 (6)

Table 5. Reason cited for discontinuation of treatment (regimen change or dropout) (n = 18) Reason

n (%)

Neuropathy

4 (22)

Neutropenia

4 (22)

Patient preference

2 (11)

Anemia

1 (6)

Death

1 (6)

Other (rash, bowel obstruction, agitation, fatigue, thrombocytopenia)

6 (33)

JANUARY JOGC JANVIER 2013 l 65

Gynaecology

but also because women with residual disease were eligible to participate, reflecting a realistic population.12 A recently presented update from this group confirmed an overall survival advantage over five years in the group of women who received dose-dense treatment (58.6% vs. 51.0%).13 As further evidence of the advantage of this treatment protocol, Dalton et al. recently published an economic analysis of dose-dense paclitaxel and carboplatin for the treatment of advanced ovarian cancer.17 Using a Markov model, weekly paclitaxel was found to be a cost-effective treatment alternative to three-weekly paclitaxel with carboplatin. Because there was often difficulty initiating intraperitoneal chemotherapy at our peripheral centres, the TBCC in 2010 adopted the dose-dense regimen of Katsumata et al. for the treatment of advanced ovarian cancer. The TBCC was among the first cancer centres in North America to do so, and to our knowledge there have been no other publications detailing the practical experience of using this protocol. In our cohort, patient age, Eastern Cooperative Oncology Group performance status,18 stage of disease, and histological characteristics were similar to those reported by Katsumata et al.12 More women in our cohort had surgical debulking to either < 1 cm or to microscopic residual disease. Proportionally more women in the Japanese Gynecologic Oncology Group trial had “suboptimal” cytoreduction than in our cohort. We anticipate that this may allow longer survival in our patients than in the cohort of Katsumata et al. Fatigue, neuropathy, and neutropenia were the most commonly reported grade 3 or 4 events. We consistently supplemented magnesium after noting profound hypomagnesemia in our initial patients. By using prophylactic filgrastim, only 35% of patients experienced grade 3 or 4 neutropenia, compared with 92% of women in the cohort of Katsumata et al.12 A similar proportion of women were able to complete the regimen as planned (61% in our cohort compared to 62% in the cohort of Katsumata et al.12), despite the fact that treatment thresholds were higher at our centre (ANC of 1.5 × 109 cells/L vs. ANC of 1.0 × 109 cells/L). Our study has limitations because of its retrospective nature. The purpose of our review was not to make any predictions about survival, although we anticipate better outcomes in this cohort than in those who received standard chemotherapy. Instead, it illustrates how this protocol can be adopted easily in a busy outpatient setting. Having gained experience with our first patients, we have made a number of modifications to the original protocol, including adding regular administration of magnesium 66 l JANUARY JOGC JANVIER 2013

and giving prophylactic filgrastim. We found that these modifications allowed the majority of our patients to complete the regimen with minimal delay. In both publicly funded and private health care systems, much attention is paid to resource allocation. Because of the more frequent dosing and potential greater toxicities, there is theoretical concern about increased cost with this type of protocol. The Markov model by Dalton17 suggests that even in this era of fiscal conservatism, this therapy is a credible option. CONCLUSION

We found carboplatin with dose-dense paclitaxel chemotherapy to be a feasible alternative protocol with acceptable toxicity in our population of women with advanced ovarian cancer. We will continue to offer this protocol to our patients and to monitor their progress. REFERENCES 1. Barnholtz-Sloan JS, Schwartz AG, Qureshi F, Jacques S, Malone J, Munkarah AR. Ovarian cancer: changes in patterns at diagnosis and relative survival over the last three decades. Am J Obstet Gynecol 2003;189:1120–7. 2. Liu J, Matulonis UA. New advances in ovarian cancer. Oncology (Williston Park) 2010;24:721–8. 3. Chi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 2006;103:559–64. 4. Stuart GC, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J, et al. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 2011;21:750–5. 5. Markman M. Role of chemotherapy in epithelial ovarian cancer. Minerva Ginecol 2011;63:287–97. 6. Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006 Jan 25;(1):CD005340. 7. Hess LM, Benham-Hutchins M, Herzog TJ, Hsu CH, Malone DC, Skrepnek GH, et al. A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer. Int J Gynecol Cancer 2007;17:561–70. 8. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. 9. Marchetti P, Urien S, Cappellini GA, Ronzino G, Ficorella C. Weekly administration of paclitaxel: theoretical and clinical basis. Crit Rev Oncol Hematol 2002;44(Suppl):S3–S13. 10. van der Burg ME, van der Gaast A, Vergote I, Burger CW, van Doorn HC, de Wit R, et al. What is the role of dose-dense therapy? Int J Gynecol Cancer 2005;15(Suppl 3):233–40. 11. Rose PG, Smrekar M, Fusco N. A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma. Gynecol Oncol 2005;96:296–300.

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

12. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. 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;374:1331–8. 13. Katsumata N, Yasuda M, Isonishi S, Michimae H, Kimura E, Aoki D, et al. Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. J Clin Oncol 2012;30(15 Suppl):5003. 14. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, Available at: http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcaev3.pdf

15. Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–56. 16. Jakobsen A, Bertelsen K, Andersen JE, Havsteen H, Jakobsen P, Moeller KA, et al. Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study. J Clin Oncol 1997;15:193–8. 17. Dalton HJ, Yu X, Hu L, Kapp DS, Benjamin I, Monk BJ, et al. An economic analysis of dose dense weekly paclitaxel plus carboplatin versus every-3-week paclitaxel plus carboplatin in the treatment of advanced ovarian cancer. Gynecol Oncol 2012;124:199–204. 18. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.

JANUARY JOGC JANVIER 2013 l 67