**3.1. History of chemotherapy**

Twenty years ago, patients with advanced ovarian cancer were treated most commonly with the alkylating agents such as cyclophosphamide, chlorambucil, thiotepa and melphalan, all as monotherapy. These drugs have resulted in overall objective response rates between 33 and 65% and complete clinical responses in nearly 20% of patients [2].

In 1970, cisplatin was established by Wiltshaw and Kroner [3] as one of the most active agents for ovarian cancer, with a reported overall response rate of 26.5% in 34 patients who were resistant to alkylating agents. Moreover, Young et al. [2] obtained objective responses (one was complete) in 29% of 25 patients refractory to alkylating agents.

The North Thames Cooperative Group reported in 1985 the results of the first randomized comparison of first-line cisplatin and an alkylating agent cyclophosphamide in women with advanced ovarian cancer, it demonstrated significantly longer survival and response duration rates in patients receiving platinum therapy [4].

#### **3.2. Which platinum: carboplatin or cisplatin?**

The meta-analysis of the advanced ovarian cancer trialists group and two trials comparing cisplatinum with cyclophosphamide and carboplatin + cyclophosphamide showed that cisplatin and carboplatin have the same activity in ovarian cancer [1].

#### **3.3. What is the effective dose of platinum?**

A retrospective review reported a significant correlation between the dose intensity of cisplatin and response rates and survival [4]. Data from 10 trials focusing on platinum agents in approximately 2000 patients showed improvements in outcomes with doses up to 25 mg/m2 /week [5]. When the dose is increased above this there is increasing toxicity but without any clinical benefit observed [5]. In respect to carboplatin, clinicians use AUC from 5 to 7.5 [1].

#### **3.4. What drug should be combined with platinum (the role of taxane)?**

#### *3.4.1. Anthracycline*

**2. Staging**

factors determine its use in stage I or II disease.

rates in patients receiving platinum therapy [4].

**3.2. Which platinum: carboplatin or cisplatin?**

**3.3. What is the effective dose of platinum?**

to 25 mg/m2

from 5 to 7.5 [1].

**3.1. History of chemotherapy**

298 Ovarian Cancer - From Pathogenesis to Treatment

Following explorative surgery and after histological assessment, the tumor can be formally "staged" according to the size, extent and location of the cancer. Staging during surgery determines the appropriate treatment regimen and the long-term outcome (prognosis).

Recommendations for treatment after surgery are dependent on the stage of the cancer. Chemotherapy is recommended after surgery for stage III or IV ovarian cancer; certain tumor

Twenty years ago, patients with advanced ovarian cancer were treated most commonly with the alkylating agents such as cyclophosphamide, chlorambucil, thiotepa and melphalan, all as monotherapy. These drugs have resulted in overall objective response rates between 33 and

In 1970, cisplatin was established by Wiltshaw and Kroner [3] as one of the most active agents for ovarian cancer, with a reported overall response rate of 26.5% in 34 patients who were resistant to alkylating agents. Moreover, Young et al. [2] obtained objective responses (one

The North Thames Cooperative Group reported in 1985 the results of the first randomized comparison of first-line cisplatin and an alkylating agent cyclophosphamide in women with advanced ovarian cancer, it demonstrated significantly longer survival and response duration

The meta-analysis of the advanced ovarian cancer trialists group and two trials comparing cisplatinum with cyclophosphamide and carboplatin + cyclophosphamide showed that cis-

A retrospective review reported a significant correlation between the dose intensity of cisplatin and response rates and survival [4]. Data from 10 trials focusing on platinum agents in approximately 2000 patients showed improvements in outcomes with doses up

but without any clinical benefit observed [5]. In respect to carboplatin, clinicians use AUC

/week [5]. When the dose is increased above this there is increasing toxicity

**3. Chemotherapy in advanced and metastatic ovarian cancer**

65% and complete clinical responses in nearly 20% of patients [2].

was complete) in 29% of 25 patients refractory to alkylating agents.

platin and carboplatin have the same activity in ovarian cancer [1].

Five meta-analyses from 10 trials in 1702 patients compared cyclophosphamide plus cisplatin with cyclophosphamide, cisplatin and doxorubicine (C A P), a modest but significant improvement in survival was seen for the regimen using doxorubicine (overall hazard ratio 0.85, P 1/4 0.003) [5] . Most investigators in the United States abandoned the use of anthracycline in 1986 due to cardiotoxicity that may outweigh the clinical benefit [5].

#### *3.4.2. Paclitaxel*

A significant development in the treatment of ovarian cancer was the discovery of the taxane class of cytotoxics. Two randomized controlled trials of first-line cisplatin based dual therapy showed additional clinical benefit when cyclophosphamide was replaced by paclitaxel [6, 7].

The Gynecological Oncology Group (GOG) 111 trial studied 386 women with stage III suboptimally debulked or stage IV disease [6]. Whereas the intergroup OV10 trial had wider selection criteria and assessed 675 women with FIGO stage IIb, IIc, III or IV disease with or without successful debulking surgery [7].

In GOG 111, patients received paclitaxel at 135 mg/m<sup>2</sup> over 24 h with cisplatin at 75 mg/m2 or cyclophosphamide at 750 mg/m2 every 3 weeks for a total of 6 courses. The same drugs were studied in OV10 and paclitaxel was given at 175 mg/m<sup>2</sup> over 3 h. The median follow-up intervals were 38.5 and 37 months in the OV10 and GOG 111 studies, respectively; the combination of platinum and paclitaxel is more effective with respect to OS and PFS. Hence the chemotherapy regimen is based on this combination.

#### **3.5. Carboplatin as a substitute for cisplatin**

Regimens containing carboplatin and paclitaxel were generally better tolerated than cisplatin plus paclitaxel in three major studies in which the two doublets showed similar efficacity.

The Dutch/Danish study [8], treated 208 patients and Arbeitsgemeinschaft Gyneco-oncology (AGO) study [9] examined 798 patients (3 weekly paclitaxel at 175 or 185 mg/m2 given over 3 h plus cisplatin at 75 mg/m2 with carboplatin AUC 5 or 6 plus the same dose of paclitaxel). Patients in both studies had stage IIb, IV and were followed up for a median of 37 months [8]. The GOG 158 trial compared 792 eligible patients with optimal stage III disease given paclitaxel 135 mg/m2 over 24 h added to cisplatin at 75 mg/m2 with paclitaxel 175 mg/m2 over 3 hrs added to carboplatin AUC 7.5 [10].

The final results from AGO, GOG 158 and Dutch/Danish study noted little difference between treatments in the median PFS (the median overall survival was similar between treatment arms in each study), toxicities were mainly as expected, paclitaxel plus carboplatin were better tolerated [8–10].
